Banting Lecture 1986: Does a Common Mechanism Induce the Diverse Complications of Diabetes?

Winegrad, Albert I.

doi:10.2337/diab.36.3.396

Cited by 274 publications

(116 citation statements)

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“…This concept has been developed in different cell systems derived fom target organs for the complications of diabetes [26,27]. Extensive evidence has been provided that mesangial cells of the kidney glomerulus grown in high glucose media express a secretory phenotype, with increased matrix production and a decreased proliferative rate [28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

High glucose level inhibits capacitative Ca 2 + influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism

et al. 1997

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Diabetic glomerulopathy is a common long-term complication of insulin-dependent diabetes mellitus [1]. Hyperfiltration, resulting from a fall of afferent arteriolar resistances with increased glomerular capillary pressure, is an early sign of glomerular involvement [1,2]. Such haemodynamic changes are believed to result from reduced vascular sensitivity to vasoconstrictors [3]. Arteriolar relaxation could be explained by enhanced production of vasodilators, such as prostaglandins [4], or atrial natriuretic peptides [5]. Alternatively, reduced responsiveness of the contractile apparatus of the glomerulus should be considered [3,6]. Diabetologia (1997) Summary In cultured mesangial cells (MC), capacitative Ca 2 + influx via store-operated channels (SOC) is potentiated by agents that release Ca 2 + from intracellular stores, and inhibited by protein kinase C (PKC). Cells grown under high glucose conditions, as a model of the diabetic microenvironment, display reduced Ca 2 + signalling in response to vasoconstrictors, probably due to downregulation by elevated PKC activity. Since SOC might be relevant to this phenomenon, we assessed Ca 2 + influx by microfluorometry of fura-2-loaded rat MC cultured for 5 days in normal (5.5 mmol/l, NG) or high glucose (30 mmol/l, HG). The addition of 1-10 mmol/l Ca 2 + to NG cells equilibrated in Ca 2 + -free media induced an immediate Ca 2 + influx with a free cytosolic Ca 2 + ([Ca 2 + ] i ) plateau of 155 ± 50 and 318 ± 114 nmol/l, respectively. Basal influx was reduced to 88 ± 8 and 145 ± 17 nmol/l [Ca 2 + ]i (1-10 mmol/l Ca 2 + , p < 0.01) by 30 mmol/l d -glucose. This effect of HG was confirmed by Mn 2 + quenching of fura-2, indicating reduced entry of divalent cations via the capacitative pathway. Equimolar l -glucose had no effect on Ca 2 + influx, consistent with a non-osmotic mechanism.Arginine vasopressin (10 m mol/l) elicited weaker release of stored Ca 2 + and subsequent influx in HG cells (191 ± 33 vs 153 ± 24 nmol/l, 400 ± 76 vs 260 ± 33 nmol/l, 1-10 mmol/l Ca 2 + , NG/HG, p < 0.05). To examine the involvement of PKC in the effect of HG on capacitative Ca 2 + influx, the enzyme was activated or downregulated by treatment with 0.1 m mol/l phorbol myristate acetate (PMA) for 3 min or 24 h, respectively. PMA acutely inhibited Ca 2 + influx in NG cells, while PKC downregulation restored it in HG cells. Similarly, the PKC inhibitors staurosporin or H-7 normalized SOC activity in HG cells. In summary, impairment of Ca 2 + influx via SOC by HG is one mechanism of the reduced MC [Ca 2 + ] i responsiveness to vasoconstrictors. This event is mediated by PKC and may contribute to the glomerular haemodynamic changes in the initial stages of diabetes mellitus. [Diabetologia (1997) 40: 521-527]

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Section: Discussionmentioning

confidence: 99%

High glucose level inhibits capacitative Ca 2 + influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism

et al. 1997

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“…Treatment of diabetic rats with dietary myo-inositol has also been shown to improve nerve function [18][19][20][21]. This led to speculation 15 years ago that a common mechanism might induce the diverse complications of diabetes [22]. However, more recent studies have indicated that diabetic neuropathy is likely due to multiple mechanisms involving hyperglycemia and decreased insulin and C-peptide levels that effect both nerve and vascular tissue [17].…”

Section: Introductionmentioning

confidence: 99%

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

Coppey

Gellett

Davidson

et al. 2001

Journal of Diabetes Research

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Previously we have demonstrated that diabetes causes impairment in vascular function of epineurial vessels, which precedes the slowing of motor nerve conduction velocity. Treatment of diabetic rats with aldose reductase inhibitors, aminoguanidine or myo-inositol supplementation have been shown to improve motor nerve conduction velocity and/or decreased endoneurial blood flow. However, the effect these treatments have on vascular reactivity of epineurial vessels of the sciatic nerve is unknown. In these studies we examined the effect of treating streptozotocininduced rats with sorbinil, aminoguanidine or myo-inositol on motor nerve conduction velocity, endoneurial blood flow and endotheliumdependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with sorbinil, aminoguanidine or myo-inositol improved the reduction of endoneurial blood flow and motor nerve conduction velocity. However, only sorbinil treatment significantly improved the diabetes-induced impairment of acetylcholinemediated vasodilation of epineurial vessels of the sciatic nerve. All three treatments were efficacious in preventing the appropriate metabolic derangements associated with either activation of the polyol pathway or increased nonenzymatic glycation. In addition, sorbinil was shown to prevent the diabetes-induced decrease in lens glutathione level. However, other mark-____________________ *Corresponding author: 3 E 17 Veterans Affairs Medical Center, Iowa City, IA 52246; tel: (319) 338-0581 ext. 7629; fax: (319) 339-7025; e-mail: myorek@icva.gov Int. Jnl. Experimental Diab. Res., 3:21-36, 2002 © 2002 Taylor and Francis 1560 ers of oxidative stress were not vividly improved by these treatments. These studies suggest that sorbinil treatment may be more effective in preventing neural dysfunction in diabetes than either aminoguanidine or myoinositol.Key words: diabetes, diabetic neuropathy, endothelium, vascular reactivity, aldose reductase inhibitor, aminoguanidine INTRODUCTIONDiabetic neuropathy is a multifactorial problem likely due to the poor control of hyperglycemia. Two of these perturbations are the activation of the polyol pathway by which glucose is metabolized to sorbitol via aldose reductase contributing to an alteration in the redox balance and a decrease in myo-inositol uptake and content and an increase in non-enzymatic glycation leading to the abnormal glycation of proteins [1,2]. In animal models of diabetes prevention of these defects by treatment with aldose reductase inhibitors, aminoguanidine or supplementation with myo-inositol has been shown to improve peripheral neuropathy.Studies from numerous laboratories have shown that treating diabetic rats with an aldose reductase inhibitor improves nerve function as well as endoneurial blood flow [3][4][5][6][7][8][9][10][11][12]. This has led to wide speculation regarding the potential benefit of aldose reductase inhibitor treatment of diabetic complications [10][11][12][13][14][15][16]. However, clinical tri...

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“…A large body of evidence indicates that multiple metabolic imbalances associated with elevated tissue glucose levels contribute to the pathogenesis of diabetic vascular complications (reviewed in [1][2][3][4][5]. Many of these metabolic perturbations have been linked to increased flux of glucose via the sorbitol pathway, a two-step enzymatic process in which D -glucose is reduced to sorbitol (coupled to oxidation of NADPH to NADP ϩ ) by aldose reductase followed by the subsequent oxidation of sorbitol to fructose (coupled to reduction of NAD ϩ to NADH) by sorbitol dehydrogenase.…”

Section: Introductionmentioning

confidence: 99%

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

Tilton¹,

Kawamura²,

Chang³

et al. 1997

J. Clin. Invest.

175

143

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The purpose of these experiments was to investigate a potential role for vascular endothelial growth factor (VEGF) in mediating vascular dysfunction induced by increased glucose flux via the sorbitol pathway. Skin chambers were mounted on the backs of Sprague-Dawley rats and 1 wk later, granulation tissue in the chamber was exposed twice daily for 7 d to 5 mM glucose, 30 mM glucose, or 1 mM sorbitol in the presence and absence of neutralizing VEGF antibodies. Albumin permeation and blood flow were increased two-to three-fold by 30 mM glucose and 1 mM sorbitol; these increases were prevented by coadministration of neutralizing VEGF antibodies. Blood flow and albumin permeation were increased ‫ف‬ 2.5-fold 1 h after topical application of recombinant human VEGF and these effects were prevented by nitric oxide synthase (NOS) inhibitors (aminoguanidine and N G -monomethyl L -arginine). Topical application of a superoxide generating system increased albumin permeation and blood flow and these changes were markedly attenuated by VEGF antibody and NOS inhibitors. Application of sodium nitroprusside for 7 d or the single application of a calcium ionophore, A23187, mimicked effects of glucose, sorbitol, and VEGF on vascular dysfunction and the ionophore effect was prevented by coadministration of aminoguanidine. These observations suggest a potentially important role for VEGF in mediating vascular dysfunction induced by "hypoxia-like" cytosolic metabolic imbalances (reductive stress, increased superoxide, and nitric oxide production) linked to increased flux of glucose via the sorbitol pathway. ( J. Clin. Invest. 1997. 99:2192-2202.)

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Banting Lecture 1986: Does a Common Mechanism Induce the Diverse Complications of Diabetes?

Cited by 274 publications

References 0 publications

High glucose level inhibits capacitative Ca 2 + influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism

High glucose level inhibits capacitative Ca 2 + influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

Vascular dysfunction induced by elevated glucose levels in rats is mediated by vascular endothelial growth factor.

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