Publications by authors named "Hisashi Yokomizo"

10 Publications

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Bilirubin is inversely related to diabetic peripheral neuropathy assessed by sural nerve conduction study.

J Diabetes Investig 2021 May 5. Epub 2021 May 5.

Fukuoka City Health Promotion Support Center, Fukuoka, Japan.

Aims/introduction: Diagnosis of diabetic peripheral neuropathy (DPN) depends on subjective findings, certain investigations for DPN risks have not been performed enough. Bilirubin protects against vascular complications by reducing oxidative stress in diabetes, but is not fully tested for DPN. This study aimed to evaluate sural nerve conduction impairments (SNCI) as an objective DPN marker and the contribution of bilirubin to SNCI.

Materials And Methods: Using DPN-Check , SNCI was defined as a decline of amplitude potential or conduction velocity below the normal limit in 150 inpatients with diabetes. The correlations between SNCI and conventional DPN diagnosis criteria, the incidence of diabetic retinopathy/nephropathy, biomarkers for atherosclerosis, cardiac function by ultrasonic cardiogram, and bilirubin were statistically tested, followed by the comparison of logistic regression models for SNCI to find confounders with bilirubin.

Results: The incidence of SNCI was 72.0%. The sensitivity and specificity of SNCI for DPN prediagnosis by simplified criteria were 54.6 and 90.5%, respectively, and similarly corresponded with diabetic retinopathy and nephropathy (sensitivity 57.4 and 50.0%, respectively). SNCI significantly related to diabetes duration, declined estimated glomerular filtration rate, albuminuria and total bilirubin. SNCI incidence was attenuated in the higher bilirubin tertiles (89.8/65.3/54.8%, P < 0.001). Bilirubin was an independent inverse risk factor for SNCI, even after adjustment by known risk factors for DPN and markers for microvascular complications.

Conclusions: SNCI is a comprehensive marker for diabetic complications. We first showed the independent inverse relationship between bilirubin and SNCI through the independent pathway with other complications, provably reducing oxidative stress, as previously reported.
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http://dx.doi.org/10.1111/jdi.13568DOI Listing
May 2021

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

Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy.

Sci Transl Med 2019 07;11(499)

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

The Joslin Medalist Study characterized people affected with type 1 diabetes for 50 years or longer. More than 35% of these individuals exhibit no to mild diabetic retinopathy (DR), independent of glycemic control, suggesting the presence of endogenous protective factors against DR in a subpopulation of patients. Proteomic analysis of retina and vitreous identified retinol binding protein 3 (RBP3), a retinol transport protein secreted mainly by the photoreceptors, as elevated in Medalist patients protected from advanced DR. Mass spectrometry and protein expression analysis identified an inverse association between vitreous RBP3 concentration and DR severity. Intravitreal injection and photoreceptor-specific overexpression of RBP3 in rodents inhibited the detrimental effects of vascular endothelial growth factor (VEGF). Mechanistically, our results showed that recombinant RBP3 exerted the therapeutic effects by binding and inhibiting VEGF receptor tyrosine phosphorylation. In addition, by binding to glucose transporter 1 (GLUT1) and decreasing glucose uptake, RBP3 blocked the detrimental effects of hyperglycemia in inducing inflammatory cytokines in retinal endothelial and Müller cells. Elevated expression of photoreceptor-secreted RBP3 may have a role in protection against the progression of DR due to hyperglycemia by inhibiting glucose uptake via GLUT1 and decreasing the expression of inflammatory cytokines and VEGF.
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http://dx.doi.org/10.1126/scitranslmed.aau6627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132633PMC
July 2019

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

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

Overexpressing IRS1 in Endothelial Cells Enhances Angioblast Differentiation and Wound Healing in Diabetes and Insulin Resistance.

Diabetes 2016 09 23;65(9):2760-71. Epub 2016 May 23.

Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA

The effect of enhancing insulin's actions in endothelial cells (ECs) to improve angiogenesis and wound healing was studied in obesity and diabetes. Insulin receptor substrate 1 (IRS1) was overexpressed in ECs using the VE-cadherin promoter to create ECIRS1 TG mice, which elevated pAkt activation and expressions of vascular endothelial growth factor (VEGF), Flk1, and VE-cadherin in ECs and granulation tissues (GTs) of full-thickness wounds. Open wound and epithelialization rates and angiogenesis significantly improved in normal mice and high fat (HF) diet-induced diabetic mice with hyperinsulinemia in ECIRS1 TG versus wild type (WT), but not in insulin-deficient diabetic mice. Increased angioblasts and EC numbers in GT of ECIRS1 mice were due to proliferation in situ rather than uptake. GT in HF-fed diabetic mice exhibited parallel decreases in insulin and VEGF-induced pAkt and EC numbers by >50% without changes in angioblasts versus WT mice, which were improved in ECIRS1 TG mice on normal chow or HF diet. Thus, HF-induced diabetes impaired angiogenesis by inhibiting insulin signaling in GT to decrease the differentiation of angioblasts to EC, which was normalized by enhancing insulin's action targeted to EC, a potential target to improve wound healing in diabetes and obesity.
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http://dx.doi.org/10.2337/db15-1721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5001189PMC
September 2016

GLP-1 analog liraglutide protects against cardiac steatosis, oxidative stress and apoptosis in streptozotocin-induced diabetic rats.

Atherosclerosis 2015 May 18;240(1):250-9. Epub 2015 Mar 18.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Objective: Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits cardiac steatosis, oxidative stress and apoptosis in streptozotocin (STZ)-induced type 1 diabetic rats, via activation of AMPK-Sirt1 pathway.

Methods: Diabetic rats were treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Myocardial steatosis (detected by oil red O staining and myocardial triglyceride and diacylglycerol (DAG) contents assay), expression of protein kinase C (PKC), heart NAD(P)H oxidase activity, oxidative stress markers (8-hydroxy-2'-deoxyguanosine staining), apoptosis (TUNEL analysis) and genes that affect apoptosis and lipid metabolism were evaluated.

Results: Administration of liraglutide did not affect plasma glucose and insulin levels or body weights in STZ-induced diabetic rats, but normalized myocardial steatosis, expression of PKC, NAD(P)H oxidase activity, oxidative stress markers and apoptosis, all of which were significantly increased in diabetic hearts. Additionally, expression of genes mediating lipid uptake, synthesis and oxidation were increased in the diabetic hearts, and these increases were all reduced by liraglutide. In addition, liraglutide increased expression of Sirt1 and phosphorylated AMPK in the diabetic hearts.

Conclusions: Liraglutide may have a beneficial effect on cardiac steatosis, DAG-PKC-NAD(P)H pathway, oxidative stress and apoptosis via activation of AMPK-Sirt1 pathway, independently of a glucose-lowering effect.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.03.026DOI Listing
May 2015

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice.

Am J Physiol Endocrinol Metab 2014 May 1;306(10):E1163-75. Epub 2014 Apr 1.

Department of Internal Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic β-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic β-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.
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http://dx.doi.org/10.1152/ajpendo.00688.2013DOI Listing
May 2014

GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases.

Metabolism 2012 Oct 1;61(10):1422-34. Epub 2012 May 1.

Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2'-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-β (TGF-β), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-β, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.
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http://dx.doi.org/10.1016/j.metabol.2012.03.002DOI Listing
October 2012

Oligodeoxynucleotide-modified capillary for electrophoretic separation of single-stranded DNAs with a single-base difference.

Anal Sci 2003 Jan;19(1):73-7

Department of Applied Chemistry, Graduate School of Engineering, Kyushu University, 6-10-1, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.

We describe here a method of affinity capillary electrophoresis in which oligodeoxynucleotide (ODN) was immobilized onto the inner surface of the capillary. The immobilized ODN functioned successfully as an affinity ligand for sequence-based DNA separation. Six- or 12-mer ODN with a sequence complementary to one of the c-K-ras gene was used as an immobilized ligand. When the 12-mer ODN was used, the detection peak for the complementary ODN disappeared selectively, while the single-base mutant was detected as usual. In contrast, when the 6-mer ODN was used as the affinity ligand with a mixture of the complementary ODN and its single-base mutant, it was possible to detect both as completely separate peaks. That is, the separation mode was dependent on the base number of the immobilized ODN used as an affinity ligand.
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http://dx.doi.org/10.2116/analsci.19.73DOI Listing
January 2003