Publications by authors named "Christian Rask-Madsen"

47 Publications

Homozygous receptors for insulin and not IGF-1 accelerate intimal hyperplasia in insulin resistance and diabetes.

Nat Commun 2019 09 27;10(1):4427. Epub 2019 Sep 27.

Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.
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http://dx.doi.org/10.1038/s41467-019-12368-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765023PMC
September 2019

Insulin transport across the blood-brain barrier can occur independently of the insulin receptor.

J Physiol 2018 10 28;596(19):4753-4765. Epub 2018 Aug 28.

Research and Development, VA Puget Sound, Seattle, WA, USA.

Key Points: Insulin enters the brain from the blood via a saturable transport system. It is unclear how insulin is transported across the blood-brain barrier (BBB). Using two models of the signalling-related insulin receptor loss or inhibition, we show insulin transport can occur in vivo without the signalling-related insulin receptor. Insulin in the brain has multiple roles including acting as a metabolic regulator and improving memory. Understanding how insulin is transported across the BBB will aid in developing therapeutics to further increase CNS concentrations.

Abstract: A saturable system transports insulin from blood across the blood-brain barrier (BBB) and into the central nervous system. Whether or not the classic or signalling-related insulin receptor plays a role in mediating this transport in vivo is controversial. Here, we employed kinetics methods that distinguish between transport across the brain endothelial cell and reversible luminal surface receptor binding. Using a previously established line of mice with endothelial-specific loss of the signalling-related insulin receptor (EndoIRKO) or inhibiting the insulin receptor with the selective antagonist S961, we show insulin transport across the BBB is maintained. Rates of insulin transport were similar in all groups and transport was still saturable. Unlike transport, binding of insulin to the brain endothelial cell was decreased with the loss or inhibition of the signalling-related insulin receptor. These findings demonstrate that the signalling-related insulin receptor is not required for insulin transport across the BBB.
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http://dx.doi.org/10.1113/JP276149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166047PMC
October 2018

Exogenous Insulin Infusion Can Decrease Atherosclerosis in Diabetic Rodents by Improving Lipids, Inflammation, and Endothelial Function.

Arterioscler Thromb Vasc Biol 2018 01 21;38(1):92-101. Epub 2017 Nov 21.

From the Dianne Nunnally Hoppes Laboratory, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA.

Objective: The objective of this study is to evaluate whether exogenously induced hyperinsulinemia may increase the development of atherosclerosis.

Approach And Results: Hyperinsulinemia, induced by exogenous insulin implantation in high-fat fed (60% fat HFD) apolipoprotein E-deficient mice (ApoE) mice, exhibited insulin resistance, hyperglycemia, and hyperinsulinemia. Atherosclerosis was measured by the accumulation of fat, macrophage, and extracellular matrix in the aorta. After 8 weeks on HFD, ApoE mice were subcutaneously implanted with control (sham) or insulin pellet, and phlorizin, a sodium glucose cotransporters inhibitor (1/2)inhibitor, for additional 8 weeks. Intraperitoneal glucose tolerance test showed that plasma glucose levels were lower and insulin and IGF-1 (insulin-like growth factor-1) levels were 5.3- and 3.3-fold higher, respectively, in insulin-implanted compared with sham-treated ApoE mice. Plasma triglyceride, cholesterol, and lipoprotein levels were decreased in mice with insulin implant, in parallel with increased lipoprotein lipase activities. Atherosclerotic plaque by en face and complexity staining showed significant reductions of fat deposits and expressions of vascular adhesion molecule-1, tumor necrosis factor-α, interleukin 6, and macrophages in arterial wall while exhibiting increased activation of pAKT and endothelial nitric oxide synthase (<0.05) comparing insulin-implanted versus sham HFD ApoE mice. No differences were observed in atherosclerotic plaques between phlorizin-treated and sham HFD ApoE mice, except phlorizin significantly lowered plasma glucose and glycated hemoglobin levels while increased glucosuria. Endothelial function was improved only by insulin treatment through endothelial nitric oxide synthase/nitric oxide activations and reduced proinflammatory (M1) and increased anti-inflammatory (M2) macrophages, which were inhibited by endothelial nitric oxide synthase inhibitor.

Conclusions: Exogenous insulin decreased atherosclerosis by lowering inflammatory cytokines, macrophages, and plasma lipids in HFD-induced hyperlipidemia, insulin resistant and mildly diabetic ApoE mice.
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http://dx.doi.org/10.1161/ATVBAHA.117.310291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791542PMC
January 2018

Endothelial insulin receptors differentially control insulin signaling kinetics in peripheral tissues and brain of mice.

Proc Natl Acad Sci U S A 2017 10 18;114(40):E8478-E8487. Epub 2017 Sep 18.

Section in Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215;

Insulin receptors (IRs) on endothelial cells may have a role in the regulation of transport of circulating insulin to its target tissues; however, how this impacts on insulin action in vivo is unclear. Using mice with endothelial-specific inactivation of the IR gene (EndoIRKO), we find that in response to systemic insulin stimulation, loss of endothelial IRs caused delayed onset of insulin signaling in skeletal muscle, brown fat, hypothalamus, hippocampus, and prefrontal cortex but not in liver or olfactory bulb. At the level of the brain, the delay of insulin signaling was associated with decreased levels of hypothalamic proopiomelanocortin, leading to increased food intake and obesity accompanied with hyperinsulinemia and hyperleptinemia. The loss of endothelial IRs also resulted in a delay in the acute hypoglycemic effect of systemic insulin administration and impaired glucose tolerance. In high-fat diet-treated mice, knockout of the endothelial IRs accelerated development of systemic insulin resistance but not food intake and obesity. Thus, IRs on endothelial cells have an important role in transendothelial insulin delivery in vivo which differentially regulates the kinetics of insulin signaling and insulin action in peripheral target tissues and different brain regions. Loss of this function predisposes animals to systemic insulin resistance, overeating, and obesity.
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http://dx.doi.org/10.1073/pnas.1710625114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635907PMC
October 2017

Regulation of Macrophage Apoptosis and Atherosclerosis by Lipid-Induced PKCδ Isoform Activation.

Circ Res 2017 Oct 30;121(10):1153-1167. Epub 2017 Aug 30.

From the Section of Vascular Cell Biology, Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA (Q.L., K.P., Y.X., W.Q., J.F., H.Y., M.K., X.W., C.R.-M., G.L.K.); Department of Research and Development, SunStar, Inc, Osaka, Japan (M.M.); and Translational Research and Early Clinical Development, Cardiovascular and Metabolic Research, AstraZeneca, Mölndal, Sweden (W.Q.).

Rationale: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes mellitus and obesity contributes to the development of atherosclerosis. PKCδ (protein kinase C δ) expression and activity in monocytes were increased by hyperlipidemia and diabetes mellitus with unknown consequences to atherosclerosis.

Objective: To investigate the effect of PKCδ activation in macrophages on the severity of atherosclerosis.

Methods And Results: PKCδ expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKCδ in macrophages were generated by breeding PKCδ flox/flox mice with LyzM-Cre and ApoE mice (MPKCδKO/ApoE mice) and studied in atherogenic (AD) and high-fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD-fed mice had insulin resistance and mild diabetes mellitus. Surprisingly, MPKCδKO/ApoE mice exhibited accelerated aortic atherosclerotic lesions by 2-fold versus ApoE mice on AD or HFD. Splenomegaly was observed in MPKCδKO/ApoE mice on AD and HFD but not on regular chow. Both the AD or HFD increased macrophage number in aortic plaques and spleen by 1.7- and 2-fold, respectively, in MPKCδKO/ApoE versus ApoE mice because of decreased apoptosis (62%) and increased proliferation (1.9-fold), and not because of uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCδKO/ApoE were associated with elevated phosphorylation levels of prosurvival cell-signaling proteins, Akt and FoxO3a, with reduction of proapoptotic protein Bim associated with PKCδ induced inhibition of P85/PI3K.

Conclusions: Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKCδ isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.311606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176491PMC
October 2017

SHP-1 activation inhibits vascular smooth muscle cell proliferation and intimal hyperplasia in a rodent model of insulin resistance and diabetes.

Diabetologia 2017 03 9;60(3):585-596. Epub 2016 Dec 9.

Research Division, Joslin Diabetes Center, Harvard Medical School, Dianne Nunnally Hoppes Laboratories, One Joslin Place, Boston, MA, 02215, USA.

Aims/hypothesis: Accelerated migration and proliferation of vascular smooth muscle cells (VSMCs) enhances arterial restenosis after angioplasty in insulin resistance and diabetes. Elevation of Src homology 2-containing protein tyrosine phosphatase 1 (SHP-1) induces apoptosis in the microvasculature. However, the role of SHP-1 in intimal hyperplasia and restenosis has not been clarified in insulin resistance and diabetes.

Methods: We used a femoral artery wire injury mouse model, rodent models with insulin resistance and diabetes, and patients with type 2 diabetes. Further, we modulated SHP-1 expression using a transgenic mouse that overexpresses SHP-1 in VSMCs (Shp-1-Tg). SHP-1 agonists were also employed to study the molecular mechanisms underlying the regulation of SHP-1 by oxidised lipids.

Results: Mice fed a high-fat diet (HFD) exhibited increased femoral artery intimal hyperplasia and decreased arterial SHP-1 expression compared with mice fed a regular diet. Arterial SHP-1 expression was also decreased in Zucker fatty rats, Zucker diabetic fatty rats and in patients with type 2 diabetes. In primary cultured VSMCs, oxidised LDL suppressed SHP-1 expression by activating Mek-1 (also known as Map2k1) and increased DNA methylation of the Shp-1 promoter. VSMCs from Shp-1-Tg mice exhibited impaired platelet-derived growth factor (PDGF)-stimulated tyrosine phosphorylation with a concomitant decrease in PDGF-stimulated VSMC proliferation and migration. Similarly, HFD-fed Shp-1-Tg mice and mice treated with the SHP-1 inducer, Icariside II, were protected from the development of intimal hyperplasia following wire injury.

Conclusions/interpretation: Suppression of SHP-1 by oxidised lipids may contribute to the excessive VSMC proliferation, inflammatory cytokine production and intimal hyperplasia observed in arteries from diabetes and insulin resistance. Augmenting SHP-1 levels is a potential therapeutic strategy to maintain stent patency in patients with insulin resistance and diabetes.
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http://dx.doi.org/10.1007/s00125-016-4159-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5672905PMC
March 2017

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice.

J Surg Res 2016 09 8;205(1):49-58. Epub 2016 Jun 8.

Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.

Background: Obesity and type 2 diabetes are major risk factors for peripheral arterial disease in humans, which can result in lower limb demand ischemia and exercise intolerance. Exercise triggers skeletal muscle adaptation including increased vasculogenesis. The goal of this study was to determine whether demand ischemia modulates revascularization, fiber size, and signaling pathways in the ischemic hind limb muscles of mice with diet-induced obesity (DIO).

Materials And Methods: DIO mice (n = 7) underwent unilateral femoral artery ligation and recovered for 2 wks followed by 4 wks with daily treadmill exercise to induce demand ischemia. A parallel sedentary ischemia (SI) group (n = 7) had femoral artery ligation without exercise. The contralateral limb muscles of SI served as control. Muscles were examined for capillary density, myofiber cross-sectional area, cytokine levels, and phosphorylation of STAT3 and ERK1/2.

Results: Exercise significantly enhanced capillary density (P < 0.01) and markedly lowered cross-sectional area (P < 0.001) in demand ischemia compared with SI. These findings coincided with a significant increase in granulocyte colony-stimulating factor (P < 0.001) and interleukin-7 (P < 0.01) levels. In addition, phosphorylation levels of STAT3 and ERK1/2 (P < 0.01) were increased, whereas UCP1 and monocyte chemoattractant protein-1 protein levels were lower (P < 0.05) without altering vascular endothelial growth factor and tumor necrosis factor alpha protein levels. Demand ischemia increased the PGC1α messenger RNA (P < 0.001) without augmenting PGC1α protein levels.

Conclusions: Exercise-induced limb demand ischemia in the setting of DIO causes myofiber atrophy despite an increase in muscle capillary density. The combination of persistent increase in tumor necrosis factor alpha, lower vascular endothelial growth factor, and failure to increase PGC1α protein may reflect a deficient adaption to demand ischemia in DIO.
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http://dx.doi.org/10.1016/j.jss.2016.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021992PMC
September 2016

Insulin Downregulates the Transcriptional Coregulator CITED2, an Inhibitor of Proangiogenic Function in Endothelial Cells.

Diabetes 2016 Dec 25;65(12):3680-3690. Epub 2016 Aug 25.

Joslin Diabetes Center and Harvard Medical School, Boston, MA

In patients with atherosclerotic complications of diabetes, impaired neovascularization of ischemic tissue in the myocardium and lower limb limits the ability of these tissues to compensate for poor perfusion. We identified 10 novel insulin-regulated genes, among them Adm, Cited2, and Ctgf, which were downregulated in endothelial cells by insulin through FoxO1. CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), which was downregulated by insulin by up to 54%, is an important negative regulator of hypoxia-inducible factor (HIF) and impaired HIF signaling is a key mechanism underlying the impairment of angiogenesis in diabetes. Consistent with impairment of vascular insulin action, CITED2 was increased in cardiac endothelial cells from mice with diet-induced obesity and from db/db mice and was 3.8-fold higher in arterial tissue from patients with type 2 diabetes than control subjects without diabetes. CITED2 knockdown promoted endothelial tube formation and endothelial cell proliferation, whereas CITED2 overexpression impaired HIF activity in vitro. After femoral artery ligation, induction of an endothelial-specific HIF target gene in hind limb muscle was markedly upregulated in mice with endothelial cell deletion of CITED2, suggesting that CITED2 can limit HIF activity in vivo. We conclude that vascular insulin resistance in type 2 diabetes contributes to the upregulation of CITED2, which impairs HIF signaling and endothelial proangiogenic function.
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http://dx.doi.org/10.2337/db16-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127242PMC
December 2016

Insulin decreases atherosclerosis by inducing endothelin receptor B expression.

JCI Insight 2016 May;1(6)

Dianne Nunnally Hoppes Laboratory Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

Endothelial cell (EC) insulin resistance and dysfunction, caused by diabetes, accelerates atherosclerosis. It is unknown whether specifically enhancing EC-targeted insulin action can decrease atherosclerosis in diabetes. Accordingly, overexpressing insulin receptor substrate-1 (IRS1) in the endothelia of mice () increased insulin signaling and function in the aorta. Atherosclerosis was significantly reduced in mice on diet-induced hyperinsulinemia and hyperglycemia. The mechanism of insulin's enhanced antiatherogenic actions in EC was related to remarkable induction of NO action, which increases endothelin receptor B (EDNRB) expression and intracellular [Ca]. Using the mice with knockin mutation of eNOS, which had Ser1176 mutated to alanine (AKI), deleting the only known mechanism for insulin to activate eNOS/NO pathway, we observed that IRS1 overexpression in the endothelia of mice significantly decreased atherosclerosis. Interestingly, endothelial EDNRB expression was selectively reduced in intima of arteries from diabetic patients and rodents. However, endothelial EDNRB expression was upregulated by insulin via P13K/Akt pathway. Finally EDNRB deletion in EC of and mice decreased NO production and accelerated atherosclerosis, compared with mice. Accelerated atherosclerosis in diabetes may be reduced by improving insulin signaling selectively via IRS1/Akt in the EC by inducing EDNRB expression and NO production.
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http://dx.doi.org/10.1172/jci.insight.86574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869734PMC
May 2016

Serine phosphorylation sites on IRS2 activated by angiotensin II and protein kinase C to induce selective insulin resistance in endothelial cells.

Mol Cell Biol 2013 Aug 17;33(16):3227-41. Epub 2013 Jun 17.

Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

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.
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http://dx.doi.org/10.1128/MCB.00506-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753901PMC
August 2013

Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-β isoform in the endothelium.

Circ Res 2013 Aug 11;113(4):418-27. Epub 2013 Jun 11.

Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Rationale: Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions.

Objective: To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.

Methods And Results: Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE-/- mice [Tg (Prkcb)apoE-/-]. On a Western diet, Tg(Prkcb)apoE-/- and apoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE-/- mice was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with apoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE-/- mice increased by ≈70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix.

Conclusions: Specific protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.
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http://dx.doi.org/10.1161/CIRCRESAHA.113.301074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893704PMC
August 2013

Vascular complications of diabetes: mechanisms of injury and protective factors.

Cell Metab 2013 Jan;17(1):20-33

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.

In patients with diabetes, atherosclerosis is the main reason for impaired life expectancy, and diabetic nephropathy and retinopathy are the largest contributors to end-stage renal disease and blindness, respectively. An improved therapeutic approach to combat diabetic vascular complications might include blocking mechanisms of injury as well as promoting protective or regenerating factors, for example by enhancing the action of insulin-regulated genes in endothelial cells, promoting gene programs leading to induction of antioxidant or anti-inflammatory factors, or improving the sensitivity to vascular cell survival factors. Such strategies could help prevent complications despite suboptimal metabolic control.
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http://dx.doi.org/10.1016/j.cmet.2012.11.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546345PMC
January 2013

Retinal not systemic oxidative and inflammatory stress correlated with VEGF expression in rodent models of insulin resistance and diabetes.

Invest Ophthalmol Vis Sci 2012 Dec 19;53(13):8424-32. Epub 2012 Dec 19.

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Purpose: To correlate changes between VEGF expression with systemic and retinal oxidative stress and inflammation in rodent models of obesity induced insulin resistance and diabetes.

Methods: Retinal VEGF mRNA and protein levels were assessed by RT-PCR and VEGF ELISA, respectively. Urinary 8-hydroxydeoxyguanosine (8-OHdG), blood levels of C-reactive protein (CRP), malondialdehyde (MDA), and CD11b/c positive cell ratio were used as systemic inflammatory markers. Retinal expression of Nox2, Nox4, and p47phox mRNA levels were measured as oxidative stress markers. TNF-α, inter-cellular adhesion molecule-1 (ICAM-1), IL1β, and activation of nuclear factor κB (NF-κB) were used as retinal inflammatory markers.

Results: Retinal VEGF mRNA and protein expression increased in Zucker diabetic fatty (ZDF(fa/fa)) rats and streptozotosin (STZ) induced diabetic Sprague-Dawley rats, after two months of disease, but not in Zucker fatty (ZF) rats. Systemic markers of oxidative stress and inflammation were elevated in insulin resistant and diabetic rats. Some oxidative stress and inflammatory markers (TNF-α, IL-6, ICAM-1, and IL1-β) were upregulated in the retina of ZDF(fa/fa) and STZ diabetic rats after 4 months of disease. In contrast, activation of NF-κB in the retina was observed in high fat fed nondiabetic and diabetic cis-NF-κB(EGFP) mice, ZF, ZDF(fa/fa), and STZ-induced diabetic rats.

Conclusions: Only persistent hyperglycemia and diabetes increased retinal VEGF expression. Some markers of inflammation and oxidative stress were elevated in the retina and systemic circulation of obese and insulin resistant rodents with and without diabetes. Induction of VEGF and its associated retinal pathologies by diabetes requires chronic hyperglycemia and factors in addition to inflammation and oxidative stress.
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http://dx.doi.org/10.1167/iovs.12-10207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753893PMC
December 2012

Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease.

Arterioscler Thromb Vasc Biol 2012 Sep;32(9):2052-9

Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.

Impaired insulin signaling is central to development of the metabolic syndrome and can promote cardiovascular disease indirectly through development of abnormal glucose and lipid metabolism, hypertension, and a proinflammatory state. However, insulin's action directly on vascular endothelium, atherosclerotic plaque macrophages, and in the heart, kidney, and retina has now been described, and impaired insulin signaling in these locations can alter progression of cardiovascular disease in the metabolic syndrome and affect development of microvascular complications of diabetes mellitus. Recent advances in our understanding of the complex pathophysiology of insulin's effects on vascular tissues offer new opportunities for preventing these cardiovascular disorders.
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http://dx.doi.org/10.1161/ATVBAHA.111.241919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511859PMC
September 2012

Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes.

Diabetes 2012 Nov 23;61(11):2967-79. Epub 2012 Jul 23.

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.

To characterize glucagon-like peptide (GLP)-1 signaling and its effect on renal endothelial dysfunction and glomerulopathy. We studied the expression and signaling of GLP-1 receptor (GLP-1R) on glomerular endothelial cells and the novel finding of protein kinase A-dependent phosphorylation of c-Raf at Ser259 and its inhibition of angiotensin II (Ang II) phospho-c-Raf(Ser338) and Erk1/2 phosphorylation. Mice overexpressing protein kinase C (PKC)β2 in endothelial cells (EC-PKCβ2Tg) were established. Ang II and GLP-1 actions in glomerular endothelial cells were analyzed with small interfering RNA of GLP-1R. PKCβ isoform activation induced by diabetes decreased GLP-1R expression and protective action on the renal endothelium by increasing its degradation via ubiquitination and enhancing phospho-c-Raf(Ser338) and Ang II activation of phospho-Erk1/2. EC-PKCβ2Tg mice exhibited decreased GLP-1R expression and increased phospho-c-Raf(Ser338), leading to enhanced effects of Ang II. Diabetic EC-PKCβ2Tg mice exhibited greater loss of endothelial GLP-1R expression and exendin-4-protective actions and exhibited more albuminuria and mesangial expansion than diabetic controls. These results showed that the renal protective effects of GLP-1 were mediated via the inhibition of Ang II actions on cRaf(Ser259) and diminished by diabetes because of PKCβ activation and the increased degradation of GLP-1R in the glomerular endothelial cells.
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http://dx.doi.org/10.2337/db11-1824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478518PMC
November 2012

Glomerular VEGF resistance induced by PKCδ/SHP-1 activation and contribution to diabetic nephropathy.

FASEB J 2012 Jul 12;26(7):2963-74. Epub 2012 Apr 12.

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

This study characterizes the effect of glucose-induced activation of protein kinase Cδ (PKCδ) and Src homology-2 domain-containing phosphatase-1 (SHP-1) expression on vascular endothelial growth factor (VEGF) actions in glomerular podocytes in cultures and in glomeruli of diabetic rodents. Elevation of glucose levels induced PKCδ and p38 mitogen-activated protein kinase (p38 MAPK) to increase SHP-1 expression, increased podocyte apoptosis, and inhibited VEGF activation in podocytes and glomerular endothelial cells. The adverse effects of high glucose levels can be negated by molecular inhibitors of PKCδ, p38MAPK, and SHP-1 and only partially reduced by antioxidants and nuclear factor-κB (NF-κB) inhibitor. Increased PKCδ activation and SHP-1 expression correlated with loss of VEGF signaling and podocyte numbers in the glomeruli of diabetic rats and mice. In contrast, diabetic PKCδ-knockout (Prkcd(-/-)) mice did not exhibit activation of p38 MAPK and SHP-1 or inhibition of VEGF signaling in renal glomeruli. Functionally, diabetic Prkcd(-/-) mice had decreased expressions of TGFβ, VEGF, and extracellular matrix and less albuminuria than diabetic Prkcd(+/+) mice. Hyperglycemia and diabetes can cause glomerular podocyte apoptosis and endothelial dysfunction partly due to increased PKCδ/p38 MAPK activation and the expression of SHP-1 to cause VEGF resistance, independent of NF-κB activation.
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http://dx.doi.org/10.1096/fj.11-202994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382088PMC
July 2012

Hyperinsulinemia does not change atherosclerosis development in apolipoprotein E null mice.

Arterioscler Thromb Vasc Biol 2012 May 15;32(5):1124-31. Epub 2012 Mar 15.

Research Division, Joslin Diabetes Center, Boston, MA, USA.

Objective: To determine the contribution of hyperinsulinemia to atherosclerosis development.

Methods And Results: Apolipoprotein E (Apoe) null mice that had knockout of a single allele of the insulin receptor (Insr) gene were compared with littermate Apoe null mice with intact insulin receptors. Plasma insulin levels in Insr haploinsufficient/Apoe null mice were 50% higher in the fasting state and up to 69% higher during a glucose tolerance test, but glucose tolerance was not different in the 2 groups. C-peptide levels, insulin sensitivity, and postreceptor insulin signaling in muscle, liver, fat, and aorta were not different between groups, whereas disappearance in plasma of an injected insulin analog was delayed in Insr haploinsufficient/Apoe null mice, indicating that impaired insulin clearance was the primary cause of hyperinsulinemia. No differences were observed in plasma lipids or blood pressure. Despite the hyperinsulinemia, atherosclerotic lesion size was not different between the 2 groups at time points up to 52 weeks of age when measured as en face lesion area in the aorta, cross-sectional plaque area in the aortic sinus, and cholesterol abundance in the brachiocephalic artery.

Conclusions: Hyperinsulinemia, without substantial vascular or whole-body insulin resistance and without changes in plasma lipids or blood pressure, does not change susceptibility to atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.111.239558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640325PMC
May 2012

The effect of chronic heart failure and type 2 diabetes on insulin-stimulated endothelial function is similar and additive.

Vasc Health Risk Manag 2011 19;7:771-6. Epub 2011 Dec 19.

Department of Cardiology, Gentofte Hospital, Denmark.

Aim: Chronic heart failure is associated with endothelial dysfunction and insulin resistance. The aim of this investigation was to study insulin-stimulated endothelial function and glucose uptake in skeletal muscles in patients with heart failure in comparison to patients with type 2 diabetes.

Methods: Twenty-three patients with systolic heart failure and no history of diabetes, seven patients with both systolic heart failure and type 2 diabetes, 19 patients with type 2 diabetes, and ten healthy controls were included in the study. Endothelial function was studied by venous occlusion plethysmography. Insulin-stimulated endothelial function was assessed after intra-arterial infusion of insulin followed by co-infusion with serotonin in three different dosages. Forearm glucose uptake was measured during the insulin infusion.

Results: Patients with systolic heart failure had impaired insulin-stimulated endothelial function. The percentage increase in blood flow during co-infusion with insulin and serotonin dose response study was 24.74% ± 6.16%, 23.50% ± 8.32%, and 22.29% ± 10.77% at the three doses respectively, compared to the healthy control group 45.96% ± 11.56%, 67.40% ± 18.11% and 84.57% ± 25.73% (P = 0.01). Insulin-stimulated endothelial function was similar in heart failure patients and patients with type 2 diabetes, while it was further deteriorated in patients suffering from both heart failure and diabetes with a percentage increase in blood flow of 19.15% ± 7.81%, -2.35% ± 11.76%, and 5.82% ± 17.70% at the three doses of serotonin, respectively. Forearm glucose uptake was impaired in patients with heart failure compared to healthy controls (P = 0.03) and tended to be further impaired by co-existence of diabetes (P = 0.08).

Conclusion: Systolic heart failure and type 2 diabetes result in similar vascular insulin resistance and reduced muscular insulin-stimulated glucose uptake. The effects of systolic heart failure and type 2 diabetes appear to be additive.
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http://dx.doi.org/10.2147/VHRM.S25724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253770PMC
May 2012

Inhibition of insulin signaling in endothelial cells by protein kinase C-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase (PI3K).

J Biol Chem 2012 Feb 12;287(7):4518-30. Epub 2011 Dec 12.

Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02115, USA.

The regulation of endothelial function by insulin is consistently abnormal in insulin-resistant states and diabetes. Protein kinase C (PKC) activation has been reported to inhibit insulin signaling selectively in endothelial cells via the insulin receptor substrate/PI3K/Akt pathway to reduce the activation of endothelial nitric-oxide synthase (eNOS). In this study, it was observed that PKC activation differentially inhibited insulin receptor substrate 1/2 (IRS1/2) signaling of insulin's activation of PI3K/eNOS by decreasing only tyrosine phosphorylation of IRS2. In addition, PKC activation, by general activator and specifically by angiotensin II, increased the phosphorylation of p85/PI3K, which decreases its association with IRS1 and activation. Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1-mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K. Thus, PKC and angiotensin-induced phosphorylation of Thr-86 of p85/PI3K may partially inhibit the activation of PI3K/eNOS by multiple cytokines and contribute to endothelial dysfunction in metabolic disorders.
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http://dx.doi.org/10.1074/jbc.M111.286591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3281670PMC
February 2012

Endothelial function is unaffected by changing between carvedilol and metoprolol in patients with heart failure--a randomized study.

Cardiovasc Diabetol 2011 Oct 15;10:91. Epub 2011 Oct 15.

Department of Cardiology, Gentofte Hospital, Hellerup, Denmark.

Background: Carvedilol has been shown to be superior to metoprolol tartrate to improve clinical outcomes in patients with heart failure (HF), yet the mechanisms responsible for these differences remain unclear. We examined if there were differences in endothelial function, insulin stimulated endothelial function, 24 hour ambulatory blood pressure and heart rate during treatment with carvedilol, metoprolol tartrate and metoprolol succinate in patients with HF.

Methods: Twenty-seven patients with mild HF, all initially treated with carvedilol, were randomized to a two-month treatment with carvedilol, metoprolol tartrate or metoprolol succinate. Venous occlusion plethysmography, 24-hour blood pressure and heart rate measurements were done before and after a two-month treatment period.

Results: Endothelium-dependent vasodilatation was not affected by changing from carvedilol to either metoprolol tartrate or metoprolol succinate. The relative forearm blood flow at the highest dose of serotonin was 2.42 ± 0.33 in the carvedilol group at baseline and 2.14 ± 0.24 after two months continuation of carvedilol (P = 0.34); 2.57 ± 0.33 before metoprolol tartrate treatment and 2.42 ± 0.55 after treatment (p = 0.74) and in the metoprolol succinate group 1.82 ± 0.29 and 2.10 ± 0.37 before and after treatment, respectively (p = 0.27). Diurnal blood pressures as well as heart rate were also unchanged by changing from carvedilol to metoprolol tartrate or metoprolol succinate.

Conclusion: Endothelial function remained unchanged when switching the beta blocker treatment from carvedilol to either metoprolol tartrate or metoprolol succinate in this study, where blood pressure and heart rate also remained unchanged in patients with mild HF.

Trial Registration: Current Controlled Trials NCT00497003.
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http://dx.doi.org/10.1186/1475-2840-10-91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3212926PMC
October 2011

Endothelium-dependent delivery of insulin to muscle interstitium.

Cell Metab 2011 Mar;13(3):236-8

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.

Insulin contributes to skeletal muscle glucose uptake by increasing blood flow and recruiting perfused capillaries. In this issue of Cell Metabolism, Kubota et al. (2011) show that deletion of IRS-2 in endothelial cells in mice causes impaired transcapillary insulin transport, decreased insulin-stimulated glucose uptake in muscle, and mild glucose intolerance.
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http://dx.doi.org/10.1016/j.cmet.2011.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3232062PMC
March 2011

Glomerular-specific protein kinase C-β-induced insulin receptor substrate-1 dysfunction and insulin resistance in rat models of diabetes and obesity.

Kidney Int 2011 Apr 12;79(8):883-96. Epub 2011 Jan 12.

Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Insulin resistance has been associated with the progression of chronic kidney disease in both diabetes and obesity. In order to determine the cellular mechanisms contributing to this, we characterized insulin signaling in renal tubules and glomeruli during diabetic and insulin-resistant states using streptozotocin-diabetic and Zucker fatty-insulin-resistant rats. Compared with nondiabetic and Zucker lean rats, the insulin-induced phosphorylation of insulin receptor substrate-1 (IRS1), Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α were selectively inhibited in the glomeruli but not in the renal tubules of both respective models. Protein, but not mRNA levels of IRS1, was decreased only in the glomeruli of streptozotocin-diabetic rats likely due to increased ubiquitination. Treatment with the protein kinase C-β inhibitor, ruboxistaurin, enhanced insulin actions and elevated IRS1 expression. In glomerular endothelial cells, high glucose inhibited the phosphorylation of Akt, endothelial nitric oxide synthase, and glycogen synthase kinase 3α; decreased IRS1 protein expression and increased its association with ubiquitin. Overexpression of IRS1 or the addition of ruboxistaurin reversed the inhibitory effects of high glucose. Thus, loss of insulin's effect on endothelial nitric oxide synthase and glycogen synthase kinase 3α activation may contribute to the glomerulopathy observed in diabetes and obesity.
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http://dx.doi.org/10.1038/ki.2010.526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612886PMC
April 2011

Diabetes: Podocytes lose their footing.

Nature 2010 Nov;468(7320):42-4

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http://dx.doi.org/10.1038/468042aDOI Listing
November 2010

Ingestion of broccoli sprouts does not improve endothelial function in humans with hypertension.

PLoS One 2010 Aug 27;5(8):e12461. Epub 2010 Aug 27.

Department of Oncology, Copenhagen University Hospital, Herlev Hospital, Region Hovedstaden, Denmark.

Unlabelled: Ingestion of glucosinolates has previously been reported to improve endothelial function in spontaneously hypertensive rats, possibly because of an increase in NO availability in the endothelium due to an attenuation of oxidative stress; in our study we tried to see if this also would be the case in humans suffering from essential hypertension.

Methods: 40 hypertensive individuals without diabetes and with normal levels of cholesterol were examined. The participants were randomized either to ingest 10 g dried broccoli sprouts, a natural donor of glucosinolates with high in vitro antioxidative potential, for a 4 week period or to continue their ordinary diet and act as controls. Blood pressure, endothelial function measured by flow mediated dilation (FMD) and blood samples were obtained from the participants every other week and the content of glucosinolates was measured before and after the study. Measurements were blinded to treatment allocation.

Results: In the interventional group overall FMD increased from 4% to 5.8% in the interventional group whereas in the control group FMD was stable (4% at baseline and 3.9% at the end of the study). The change in FMD in the interventional group was mainly due to a marked change in FMD in two participants while the other participants did not have marked changes in FMD. The observed differences were not statistically significant. Likewise significant changes in blood pressure or blood samples were not detected between or within groups. Diastolic blood pressure stayed essentially unchanged in both groups, while the systolic blood pressure showed a small non significant decrease (9 mm Hg) in the interventional group from a value of 153 mm Hg at start.

Conclusion: Daily ingestion of 10 g dried broccoli sprouts does not improve endothelial function in the presence of hypertension in humans.

Trial Registration: Clinicaltrials.gov NCT00252018.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012461PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929197PMC
August 2010

Modulating Notch signaling to enhance neovascularization and reperfusion in diabetic mice.

Biomaterials 2010 Dec 25;31(34):9048-56. Epub 2010 Aug 25.

School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.

Diabetes can diminish the responsiveness to angiogenic factors (e.g., VEGF) important for wound healing and the treatment of ischemic diseases, and this study investigated the hypothesis that this effect can be reversed by altering Notch signaling. Aortic endothelial cells (ECs) isolated from diabetic mice demonstrated reduced sprouting capability in vitro, but adding a Notch inhibitor (DAPT) led to cell-density and VEGF-dose dependent enhancement of proliferation, migration and sprouting, in both 2-D and 3-D cultures, as compared to VEGF alone. The in vivo effects of VEGF and DAPT were tested in the ischemic hind limbs of diabetic mice. Combining VEGF and DAPT delivery resulted in increased blood vessel density (∼150%) and improved tissue perfusion (∼160%), as compared to VEGF alone. To examine if DAPT would interfere with vessel maturation, DAPT was also delivered with a combination of VEGF and platelet derived growth factor (PDGF). DAPT and PDGF did not interfere with the effects of the other, and highly functional and mature networks of vessels could be formed with appropriate delivery. In summary, modulating Notch signaling enhances neovascularization and perfusion recovery in diabetic mice suffering from ischemia, suggesting this approach could have utility for human diabetics.
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http://dx.doi.org/10.1016/j.biomaterials.2010.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2949444PMC
December 2010

Metoprolol compared to carvedilol deteriorates insulin-stimulated endothelial function in patients with type 2 diabetes - a randomized study.

Cardiovasc Diabetol 2010 May 25;9:21. Epub 2010 May 25.

Department of Medicine, Naestved Hospital, Naestved, Denmark.

Aim: Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes.

Method: 24 patients with type 2 diabetes were randomized to receive either 200 mg metoprolol succinate or 50 mg carvedilol daily. Endothelium-dependent vasodilation was assessed by using venous occlusion plethysmography with increasing doses of intra-arterial infusions of the agonist serotonin. Insulin-stimulated endothelial function was assessed after co-infusion of insulin for sixty minutes. Vaso-reactivity studies were done before and after the two-month treatment period.

Results: Insulin-stimulated endothelial function was deteriorated after treatment with metoprolol, the percentage change in forearm blood-flow was 60.19% +/- 17.89 (at the highest serotonin dosages) before treatment and -33.80% +/- 23.38 after treatment (p = 0.007). Treatment with carvedilol did not change insulin-stimulated endothelial function. Endothelium-dependent vasodilation without insulin was not changed in either of the two treatment groups.

Conclusion: This study shows that vascular insulin sensitivity was preserved during treatment with carvedilol while blunted during treatment with metoprolol in patients with type 2 diabetes.

Trial Registration: Current Controlled Trials NCT00497003.
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http://dx.doi.org/10.1186/1475-2840-9-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893119PMC
May 2010

Loss of insulin signaling in vascular endothelial cells accelerates atherosclerosis in apolipoprotein E null mice.

Cell Metab 2010 May;11(5):379-89

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.

To determine whether insulin action on endothelial cells promotes or protects against atherosclerosis, we generated apolipoprotein E null mice in which the insulin receptor gene was intact or conditionally deleted in vascular endothelial cells. Insulin sensitivity, glucose tolerance, plasma lipids, and blood pressure were not different between the two groups, but atherosclerotic lesion size was more than 2-fold higher in mice lacking endothelial insulin signaling. Endothelium-dependent vasodilation was impaired and endothelial cell VCAM-1 expression was increased in these animals. Adhesion of mononuclear cells to endothelium in vivo was increased 4-fold compared with controls but reduced to below control values by a VCAM-1-blocking antibody. These results provide definitive evidence that loss of insulin signaling in endothelium, in the absence of competing systemic risk factors, accelerates atherosclerosis. Therefore, improving insulin sensitivity in the endothelium of patients with insulin resistance or type 2 diabetes may prevent cardiovascular complications.
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http://dx.doi.org/10.1016/j.cmet.2010.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3020149PMC
May 2010

Kidney complications: factors that protect the diabetic vasculature.

Nat Med 2010 Jan;16(1):40-1

Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1038/nm0110-40DOI Listing
January 2010

Selective regulation of heme oxygenase-1 expression and function by insulin through IRS1/phosphoinositide 3-kinase/Akt-2 pathway.

J Biol Chem 2008 Dec 14;283(49):34327-36. Epub 2008 Oct 14.

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA.

Heme oxygenase 1 (HO-1) is a representative mediator of antioxidants and cytoprotectants against various stress stimuli including oxidants in vascular cells. Intensive insulin treatment can delay the onset and progression of diabetic retinopathy and other vascularopathies, yet little is known about insulin regulation of anti-apoptotic and antioxidant molecules such as HO-1 in vascular cells. Intravitreous injection or in vitro addition of insulin increased HO-1 protein expression in rat retina and in cultured bovine retinal pericytes, retinal endothelial cells, and retinal pigment epithelial cells. In bovine retinal pericytes, insulin induced mRNA and protein expression of HO-1 in a time- and concentration-dependent manner. Using HO-1 promoter analysis, the luciferase reporter assay showed that induction of HO-1 expression by insulin is mediated by additional response elements in the ho-1 promoter gene, which was not responsive to antioxidants. Insulin-induced HO-1 mRNA expression through activation of PI3-kinase/Akt pathway without affecting ERK and p38 MAPK. Overexpression of an adenoviral vector of native IRS1, IRS2, and Akt dominant negative or small interfering RNA transfection of Akt1 and Akt2 targeted gene demonstrated that insulin regulated HO-1 expression via IRS1 and Akt2 pathway, selectively. Further, insulin treatment prevented H(2)O(2)-induced NF-kappaB and caspase-8 activation and apoptosis via the IRS1/PI3K/Akt2/HO-1 pathway in the pericytes. In conclusion, we suggest that the anti-apoptotic properties of insulin are mediated partly by increasing HO-1 expression at transcriptional level via IRS1/PI3K/Akt2 activation, a potential explanation for how insulin is retarding the progression of microvascular complications induced by diabetes.
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http://dx.doi.org/10.1074/jbc.M807036200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2590690PMC
December 2008