George L King

Joslin Diabetes Center, Boston, Massachusetts, United States

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Publications (102)689.04 Total impact

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    ABSTRACT: OBJECTIVE We characterize and correlate endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) with lack of vascular complications in Joslin's Medalist Study in patients with type 1 diabetes for 50 years or longer.RESEARCH DESIGN AND METHODSEPC and CPC levels were ascertained by flow cytometry and compared among Medalists (n = 172) with or without diabetic retinopathy (DR; n = 84 of 162), neuropathy (n = 94 of 165), diabetic nephropathy (DN; n = 18 of 172), cardiovascular disease (CVD; n = 63 of 168), age-matched controls (n = 83), type 2 diabetic patients (n = 36), and younger type 1 diabetic patients (n = 31). Mitogens, inflammatory cytokines, and oxidative markers were measured in blood or urine. Migration of cultured peripheral blood mononuclear cells (PBMCs) from Medalists and age-matched controls were compared.RESULTSMedalists' EPC and CPC levels equaled their nondiabetic age-matched controls, were 10% higher than younger type 1 diabetic patients, and were 20% higher than age-matched type 2 diabetic patients. CPC levels were 15% higher in Medalists without CVD and nephropathy than those affected, whereas EPC levels were significantly higher in those without peripheral vascular disease (PVD) than those with PVD. Stromal-derived factor 1 (SDF-1) levels were higher in Medalists with CVD, DN, and DR than those not affected and their controls. IGF-I levels were lower in Medalists and correlated inversely with CPC levels. Additionally, cultured PBMCs from Medalists migrated more than nondiabetic controls.CONCLUSIONS Normal levels of EPC and CPC in the Medalists, unlike other groups with diabetes, especially those without CVD, support the idea that endogenous factors exist to neutralize the adverse effects of metabolic abnormalities of diabetes on vascular tissues.
    Diabetes care 04/2014; · 7.74 Impact Factor
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    ABSTRACT: Periodontal disease is related to aging, smoking habits, diabetes mellitus, and systemic inflammation. However, there remains limited evidence about causality from intervention studies. An effective diet for prevention of periodontal disease has not been well established. The current study was an intervention study examining the effects of a high-fiber, low-fat diet on periodontal disease markers in high-risk subjects. Forty-seven volunteers were interviewed for recruitment into the study. Twenty-one volunteers with a body mass index ≥25.0 or with impaired glucose tolerance were enrolled in the study. After a 2- to 3-week run-in period, subjects were provided with a test meal consisting of high fiber and low fat (30 kcal/kg of ideal body weight) three times a day for eight weeks and followed by a regular diet for 24 weeks. Four hundred and twenty-five teeth from 17 subjects were analyzed. Periodontal disease markers assessed as probing depth (2.28 vs. 2.21 vs. 2.13 mm; P < 0.0001), clinical attachment loss (6.11 vs. 6.06 vs. 5.98 mm; P < 0.0001), and bleeding on probing (16.2 vs. 13.2 vs. 14.6%; P = 0.005) showed significant reductions after the test-meal period, and these improvements persisted until the follow-up period. Body weight (P < 0.0001), HbA1c (P < 0.0001), and high-sensitivity C-reactive protein (P = 0.038) levels showed improvement after the test-meal period; they returned to baseline levels after the follow-up period. In conclusion, treatment with a high-fiber, low-fat diet for eight weeks effectively improved periodontal disease markers as well as metabolic profiles, at least in part, by effects other than the reduction of total energy intake.
    Nutrition Research. 01/2014;
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    ABSTRACT: The prevalence of diabetes is rising dramatically among Asians, with increased consumption of the typical Western diet as one possible cause. We explored the metabolic responses in East Asian Americans (AA) and Caucasian Americans (CA) when transitioning from a traditional Asian diet (TAD) to a typical Western diet (TWD), which has not been reported before. This 16-week randomized control pilot feasibility study, included 28AA and 22CA who were at risk of developing type 2 diabetes. Eight weeks of TAD were provided to all participants, followed by 8 weeks of isoenergy TWD (intervention) or TAD (control). Anthropometric measures, lipid profile, insulin resistance and inflammatory markers were assessed. While on TAD, both AA and CA improved in insulin AUC (-960.2 µU/mL×h, P = 0.001) and reduced in weight (-1.6 kg; P<0.001), body fat (-1.7%, P<0.001) and trunk fat (-2.2%, P<0.001). Comparing changes from TAD to TWD, AA had a smaller weight gain (-1.8 to 0.3 kg, P<0.001) than CA (-1.4 to 0.9 kg, P = 0.001), but a greater increase in insulin AUC (AA: -1402.4 to 606.2 µU/mL×h, P = 0.015 vs CA: -466.0 to 223.5 µU/mL×h, P = 0.034) and homeostatic static model assessment-insulin resistance (HOMA-IR) (AA: -0.3 to 0.2, P = 0.042 vs CA: -0.1 to 0.0, P = 0.221). Despite efforts to maintain isoenergy state and consumption of similar energy, TAD induced weight loss and improved insulin sensitivity in both groups, while TWD worsened the metabolic profile. Trial Registration: NCT00379548.
    PLoS ONE 01/2014; 9(9):e106851. · 3.53 Impact Factor
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    ABSTRACT: OBJECTIVE Vascular dysfunction is a major contributor to diabetes complications. It is also the primary physiologic cause of erectile dysfunction and considered an independent predictor of cardiovascular disease (CVD) in males over age 40. A cohort of individuals with 50 or more years of type 1 diabetes, Joslin Medalists, have low rates of small but not large vessel complications. This study aims to identify the prevalence and longitudinal association of sexual dysfunction (SD) with CVD in Joslin Medalists.RESEARCH DESIGN AND METHODS Description and association of self-assessment of SD in males of the Medalist cohort by self-reported sexual problems with CVD. SD is validated through the use of the abbreviated International Index of Erectile Dysfunction (IIEF).RESULTSOf 301 males in the Medalist Study, 69.8% reported a history of SD. Unadjusted risk factors included elevated glycated hemoglobin (HbA1c) (P = 0.02), elevated BMI (P = 0.03), higher total cholesterol (P = 0.02), lower HDL (P < 0.01), and increased levels of interleukin-6 (P = 0.03). SD was independently associated with CVD (age-, HbA1c-, and BMI-adjusted OR 1.9 [95% CI 1.0-3.5]). In adjusted analyses, retinal, neural, and renal complications were not associated (P > 0.05) with SD. Current report of SD (IIEF score ≤17) in a subset of Medalists was significantly correlated with self-reported longitudinal SD.CONCLUSIONSSD in those with extreme-duration type 1 diabetes is independently associated with CVD, representing a large vessel pattern. The findings suggest that SD may predict CVD in those with type 1 diabetes of long duration. These individuals have also been found to be relatively free of microvascular complications.
    Diabetes care 06/2013; · 7.74 Impact Factor
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    ABSTRACT: Protein Kinase C (PKC) activation, induced by hyperglycemia and angiotensin II (AngII), inhibited insulin-induced phosphorylation of Akt/eNOS by decreasing p-Tyr-IRS2 in endothelial cells. PKC activation by phorbol ester (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 (303, 343, and 675), which affected insulin-induced tyrosine phosphorylation of IRS2 at 653, 671, and 911 (p-Tyr-IRS2) and p-Akt/eNOS. Specific PKCβ2 activation decreased p-Tyr-IRS2 and increased the phosphorylation of two serine sites (303 and 675) on IRS2 that were confirmed in cells overexpressing single point mutants of IRS2 (S303A or S675A) containing PKCβ2-dominant negative, or selective PKCβ inhibitor. AngII induced phosphorylation only on Ser 303 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 of p-Ser303 and p-Ser675 and decreases in p-Tyr911 of IRS2 were observed in vessels of Zucker fatty insulin resistant vs. 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.
    Molecular and cellular biology 06/2013; · 6.06 Impact Factor
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    ABSTRACT: PurposeThe purpose of this study is to examine the effectiveness of a culturally specific pilot clinic for Asian Americans (AA) in reaching glycemic target and to characterize factors affecting the attainment of glycemic control in comparison with white counterparts.Methods This electronic health record review included all new AA patients with type 2 diabetes (n = 109) in a culturally specific program and a randomly selected sample of new white patients with type 2 diabetes (n = 218) in the adult clinic within the same time period and diabetes center.ResultsAA and whites had a comparable proportion of patients with A1C ≤7% (32.1%, 34.9%; P = .621) at baseline and after 12 months of care (48.6%, 56.0%; P = .210), with a similar A1C decline (-0.9% ± 1.6%, -0.8% ± 1.7%, P = .710) by 12 months. Factors associated with the lack of success in reaching target in AA but not in whites included older age, lower educational attainment, less likelihood of having health insurance, and a need for more educational visits. The percentage of AA reaching A1C ≤7%, as compared to whites, worsened among those with highest initial A1C when stratified by ascending quartiles (96.7% vs 85.2%, P = .101; 61.9% vs 58.9%, P = .813; 24.0% vs 37.7%, P = .230; 15.2% vs 35.4%, P = .044).Conclusion While a culturally specific diabetes program in a specialty setting achieved a similar glycemic outcome for AA compared with whites, reasons for not reaching glycemic target differed. The findings suggest that the elimination of diabetes disparities requires not only culturally and linguistically specific programs, but must also identify and address the socio-environmental differences unique to each population.
    The Diabetes Educator 06/2013; · 1.94 Impact Factor
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    ABSTRACT: Rationale: Loss of insulin action on the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes can activate protein kinase C (PKC) β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase (PI3K)/Akt pathway to inhibit the activation of endothelial nitric oxide synthase (eNOS) and metabolic actions. Objective: To demonstrate that overexpressing PKCβ2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta. Methods and Results: PKCβ2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell-cadherin (VE-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 were impaired by ~40% with respect to Akt/eNOS activation and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)ApoE(-/-) mice compared to ApoE(-/-) mice. Basal and angiotensin stimulated big endothelin-1 (ET-1) levels were elevated in Tg(Prkcb)ApoE(-/-) mice compared to 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 PKCβ2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis due to loss of insulin-stimulated Akt/eNOS activation and angiotensin induced increases in ET-1 expression.
    Circulation Research 06/2013; · 11.86 Impact Factor
  • Christian Rask-Madsen, George L King
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    ABSTRACT: 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.
    Cell metabolism 01/2013; 17(1):20-33. · 17.35 Impact Factor
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    ABSTRACT: Although excessive fructose intake is epidemiologically linked with dyslipidemia, obesity, and diabetes, the mechanisms regulating plasma fructose are not well known. Cells transfected with sodium/glucose cotransporter 5 (SGLT5), which is expressed exclusively in the kidney, transport fructose in vitro; however, the physiological role of this transporter in fructose metabolism remains unclear. To determine whether SGLT5 functions as a fructose transporter in vivo, we established a line of mice lacking the gene encoding SGLT5. Sodium-dependent fructose uptake disappeared in renal brush border membrane vesicles from SGLT5-deficient mice, and the increased urinary fructose in SGLT5-deficient mice indicated that SGLT5 was the major fructose reabsorption transporter in the kidney. From this, we hypothesized that urinary fructose excretion induced by SGLT5 deficiency would ameliorate fructose-induced hepatic steatosis. To test this hypothesis we compared SGLT5-deficient mice with wild-type mice under conditions of long-term fructose consumption. Paradoxically, however, fructose-induced hepatic steatosis was exacerbated in the SGLT5-deficient mice, and the massive urinary fructose excretion was accompanied by reduced levels of plasma triglycerides and epididymal fat but fasting hyperinsulinemia compared with fructose-fed wild-type mice. There was no difference in food consumption, water intake, or plasma fructose between the two types of mice. No compensatory effect by other transporters reportedly involved in fructose uptake in the liver and kidney were indicated at the mRNA level. These surprising findings indicated a previously unrecognized link through SGLT5 between renal fructose reabsorption and hepatic lipid metabolism.
    PLoS ONE 01/2013; 8(2):e56681. · 3.53 Impact Factor
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    ABSTRACT: Willow bark extract (WBE) is listed in the European Pharmacopoeia and has been traditionally used for treating fever, pain and inflammation. Recent studies have demonstrated its clinical usefulness. This study investigated the antioxidative effects of WBE in human umbilical vein endothelial cells (HUVECs) and Caenorhabditis elegans. WBE prevented oxidative-stress-induced cytotoxicity of HUVECs and death of C. elegans. WBE dose-dependently increased mRNA and protein expression levels of the nuclear factor erythroid 2-related factor 2 (Nrf2) target genes, heme oxygenase-1, γ-glutamyl-cysteine ligase modifier and catalytic subunits, and p62, and intracellular glutathione (GSH) in HUVECs. In the nematode C. elegans, WBE increased the expression of the gcs-1::green fluorescent protein (GFP) reporter, a well-characterized target of the Nrf2 ortholog SKN-1, in a manner that was SKN-1-dependent. WBE increased intranuclear expression and DNA binding of Nrf2, and activity of an antioxidant response element (ARE) reporter plasmid in HUVECs. WBE-induced expression of Nrf2-regulated genes, and increased GSH levels in HUVECs were reduced by Nrf2 and p38 small interfering (si)RNAs, and by the p38-specific inhibitor SB203580. Nrf2 siRNA reduced the cytoprotective effect of WBE against oxidative stress in HUVECs. Salicin, a major anti-inflammatory ingredient of WBE, failed to activate ARE-luciferase activity, while a salicin-free WBE fraction showed intensive activity. WBE induced antioxidant enzymes and prevented oxidative stress through activation of Nrf2 independently of salicin, providing a new potential explanation for the clinical usefulness of WBE.
    Free Radical Biology and Medicine 12/2012; · 5.27 Impact Factor
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    ABSTRACT: Purpose. To correlate changes between vascular endothelial growth factor (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. Tumor necrosis factor (TNF-α), inter-cellular adhesion molecule-1 (ICAM-1), IL1β and activation of 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 SD 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. TNF-α, IL-6, ICAM-1 and IL1-β were upregulated in the retina of ZDF(fa/fa) and STZ diabetic rats after four 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. Conclusion. 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.
    Investigative ophthalmology & visual science 11/2012; · 3.43 Impact Factor
  • Akira Mima, Weier Qi, George L King
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    ABSTRACT: Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.
    Seminars in Nephrology 09/2012; 32(5):471-8. · 2.83 Impact Factor
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    ABSTRACT: Transforming growth factor-beta1 (TGF-B1) is a highly pleiotropic cytokine whose functions include a central role in the induction of fibrosis. To investigate the hypothesis that elevated plasma levels of TGF-B1 are positively associated with incident heart failure (HF). The hypotheses were tested using a two-phase case-control study design, ancillary to the Cardiovascular Health Study - a longitudinal, population-based cohort study. Cases were defined as having an incident HF event after their 1992-1993 exam and controls were free of HF at follow-up. TGF-B1 was measured using plasma collected in 1992-1993 and data from 89 cases and 128 controls were used for analysis. The association between TGF-B1 and risk of HF was evaluated using the weighted likelihood method, and odds ratios (OR) for risk of HF were calculated for TGF-B1 as a continuous linear variable and across quartiles of TGF-B1. The OR for HF was 1.88 (95% confidence intervals [CI] 1.26-2.81) for each nanogram increase in TGF-B1, and the OR for the highest quartile (compared to the lowest) of TGF-B1 was 5.79 (95% CI 1.65-20.34), after adjustment for age, sex, C-reactive protein, platelet count and digoxin use. Further adjustment with other covariates did not change the results. Higher levels of plasma TGF-B1 were associated with an increased risk of incident heart failure among older adults. However, further study is needed in larger samples to confirm these findings.
    Cytokine 08/2012; 60(2):341-5. · 2.52 Impact Factor
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    ABSTRACT: 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.
    Diabetes 07/2012; 61(11):2967-79. · 7.90 Impact Factor
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    Diabetes care 05/2012; 35(5):1189-98. · 7.74 Impact Factor
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    Diabetes care 05/2012; 35(5):1181-8. · 7.74 Impact Factor
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    ABSTRACT: 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.
    The FASEB Journal 04/2012; 26(7):2963-74. · 5.70 Impact Factor
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    ABSTRACT: To determine the contribution of hyperinsulinemia to atherosclerosis development. 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. Hyperinsulinemia, without substantial vascular or whole-body insulin resistance and without changes in plasma lipids or blood pressure, does not change susceptibility to atherosclerosis.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2012; 32(5):1124-31. · 6.34 Impact Factor
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    ABSTRACT: 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.
    Journal of Biological Chemistry 12/2011; 287(7):4518-30. · 4.65 Impact Factor
  • Diabetes care 09/2011; 34(9):e149. · 7.74 Impact Factor

Publication Stats

4k Citations
689.04 Total Impact Points


  • 1998–2014
    • Joslin Diabetes Center
      • Section on Vascular Cell Biology
      Boston, Massachusetts, United States
    • Kyushu University
      • Faculty of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 1999–2013
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2006–2012
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007
    • Ankara University
      • Department of Biochemistry (Faculty of Pharmacy)
      Ankara, Ankara, Turkey
  • 2005
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 2003
    • University of Manitoba
      Winnipeg, Manitoba, Canada