Molecular Understanding of Hyperglycemia's Adverse Effects for Diabetic Complications

Sheetz, Matthew J.

doi:10.1001/jama.288.20.2579

Cited by 855 publications

(670 citation statements)

References 136 publications

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“…studies have provided strong evidence implicating the activation of PKCβ in the upregulation of VEGF expression during diabetic retinopathy (for review, see Sheetz and King, 2002). Large scale clinical trials testing the efficacy of the specific PKCβ inhibitor LY333531 for patients with diabetic retinopathy showed that the treatment reduced vision loss, need for laser treatment and macular edema progression, while increasing occurrence of visual improvement in patients with nonproliferative retinopathy (Aiello et al, 2006).…”

Section: Inhibiting Pkc-preclinicalmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

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Collectively, angiogenic ocular conditions represent the leading cause of irreversible vision loss in developed countries. In the U.S., for example, retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration are the principal causes of blindness in the infant, working age and elderly populations, respectively. Evidence suggests that vascular endothelial growth factor (VEGF), a 40 kDa dimeric glycoprotein, promotes angiogenesis in each of these conditions, making it a highly significant therapeutic target. However, VEGF is pleiotropic, affecting a broad spectrum of endothelial, neuronal and glial behaviors, and confounding the validity of anti-VEGF strategies, particularly under chronic disease conditions. In fact, among other functions VEGF can influence cell proliferation, cell migration, proteolysis, cell survival and vessel permeability in a wide variety of biological contexts. This article will describe the roles played by VEGF in the pathogenesis of retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration. The potential disadvantages of inhibiting VEGF will be discussed, as will the rationales for targeting other VEGF-related modulators of angiogenesis.

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Section: Inhibiting Pkc-preclinicalmentioning

confidence: 99%

Vascular endothelial growth factor in eye disease

Penn

Madan

Caldwell

et al. 2008

Progress in Retinal and Eye Research

636

527

View full text Add to dashboard Cite

show abstract

“…Type 1 diabetes confers a twoto tenfold increased risk of death and cardiovascular disease compared with the background population [1,2]. Diabetes is associated with endothelial dysfunction and reduced neovascularisation in response to tissue ischaemia [3,4]. It has been suggested that contributory factors to the pathogenesis of atherosclerosis include postprandial glucose levels and arterial wall inflammation [5,6].…”

Section: Introductionmentioning

confidence: 99%

Circulating endothelial progenitor cells, endothelial function, carotid intima–media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria

et al. 2009

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Aims/hypothesis Type 1 diabetes is associated with premature arterial disease. Bone-marrow derived, circulating endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair. The hypothesis tested was that circulating EPCs are reduced in young people with type 1 diabetes without vascular injury and that this is associated with impaired endothelial function and increased carotid intima-media thickness (CIMT). Methods We compared 74 people with type 1 diabetes with 80 healthy controls. CD34, CD133, vascular endothelial (VE) growth factor receptor-2 (VEGFR-2) and VE-cadherin antibodies were used to quantify EPCs and progenitor cell subtypes using flow-cytometry. Ultrasound assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and CIMT was made. Circulating endothelial markers, inflammatory markers and plasma plasminogen activator inhibitor-1 (PAI-1) levels were measured. Results CD34+VE-cadherin+, CD133+VE-cadherin+ and CD133+VEGFR-2+ EPC counts were significantly lower in people with diabetes (46-69%; p=0.004-0.043). In people with type 1 diabetes, FMD was reduced by 45% (p<0.001) and CIMT increased by 25% (p<0.001), these being correlated (r=−0.25, p=0.033). There was a significant relationship between FMD and CD34+VE-cadherin+ (r = 0.39, p = 0.001), CD133+VEGFR-2+ (r =0.25, p = 0.037) and CD34+ (r=0.34, p=0.003) counts. Circulating high-sensitivity C-reactive protein, PAI-1, interleukin-6 and E-selectin were significantly higher in the diabetes group (p < 0.001 to p = 0.049), the last two of these correlating with FMD (r=−0.27, p=0.028 and r=−0.24, p=0.048, respectively). Conclusions/interpretation These findings suggest that abnormalities of endothelial function in addition to proinflammatory and pro-thrombotic states are already common in people with type 1 diabetes before development of clinically evident arterial damage. Low EPC counts confirm risk of macrovascular complications and may account for impaired endothelial function and predict future cardiovascular events.

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“…Type 2 diabetes is characterised by insulin resistance and accumulation of fat in parenchymal organs. Many of the pathogenic theories on causes of DN in type 2 diabetes relate to chronic hyperglycaemia and its associated toxic effects on target organs [2]. In addition, insulin resistance is an early and pivotal change [3].…”

Section: Introductionmentioning

confidence: 99%

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

et al. 2007

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Aims/hypothesis In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy. Materials and methods Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR.Results Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulinlike growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulindriven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals. Conclusions/interpretation Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.

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Molecular Understanding of Hyperglycemia's Adverse Effects for Diabetic Complications

Cited by 855 publications

References 136 publications

Vascular endothelial growth factor in eye disease

Vascular endothelial growth factor in eye disease

Circulating endothelial progenitor cells, endothelial function, carotid intima–media thickness and circulating markers of endothelial dysfunction in people with type 1 diabetes without macrovascular disease or microalbuminuria

Systemic and renal growth hormone–IGF1 axis involvement in a mouse model of type 2 diabetes

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