Diabetic Microvascular Disease Research Articles

PKC inhibition and diabetic microvascular complications

In patients with diabetes, the hyperglycaemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to production of vascular endothelial growth factor (VEGF) in the retina. PKC activation is likely to play a key role in diabetic microvascular complications, particularly changes in vascular permeability and ischaemia in the retina. A new potential therapeutic agent, the PKC-beta inhibitor ruboxistaurin, has been studied in animal and human clinical trials in diabetic microvascular disease, particularly in patients with diabetic retinopathy. The mechanism of action of PKC and the results of these trials are discussed in this review. Ruboxistaurin shows promise as an oral treatment for diabetic retinopathy. The trials have demonstrated a significant reduction in visual loss and need for laser treatment in patients with moderate to severe diabetic retinopathy over a 3-year period. There have been no significant concerns over safety or the side-effects profile in the clinical trials. Ruboxistaurin currently has approvable status pending further randomized trials defined by the US Food and Drug Administration (FDA).

Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia

BackgroundAdvanced glycation end-products (AGEs) and their receptor (RAGE) occur in dementia of the Alzheimer's type and diabetic microvascular disease. Accumulation of AGEs relates to risk factors for vascular dementia with ageing, including hypertension and diabetes. Cognitive dysfunction in vascular dementia may relate to microvascular disease resembling that in diabetes. We tested if, among people with cerebrovascular disease, (1) those with dementia have higher levels of neuronal and vascular AGEs and (2) if cognitive dysfunction depends on neuronal and/or vascular AGE levels.MethodsBrain Sections from 25 cases of the OPTIMA (Oxford Project to Investigate Memory and Ageing) cohort, with varying degrees of cerebrovascular pathology and cognitive dysfunction (but only minimal Alzheimer type pathology) were immunostained for Nε-(carboxymethyl)-lysine (CML), the most abundant AGE. The level of staining in vessels and neurons in the cortex, white matter and basal ganglia was compared to neuropsychological and other clinical measures.ResultsThe probability of cortical neurons staining positive for CML was higher in cases with worse cognition (p = 0.01) or a history of hypertension (p = 0.028). Additionally, vascular CML staining related to cognitive impairment (p = 0.02) and a history of diabetes (p = 0.007). Neuronal CML staining in the basal ganglia related to a history of hypertension (p = 0.002).ConclusionCML staining in cortical neurons and cerebral vessels is related to the severity of cognitive impairment in people with cerebrovascular disease and only minimal Alzheimer pathology. These findings support the possibility that cerebral accumulation of AGEs may contribute to dementia in people with cerebrovascular disease.

Expression profile of total VEGF, VEGF splice variants and VEGF receptors in the myocardium and arterial vasculature of diabetic and non-diabetic patients with coronary artery disease

Background: Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis and is implicated in the development of diabetic microvascular and macrovascular disease. Methods: The expression of total VEGF, VEGF splice variants (VEGF 121, VEGF 145, VEGF 148, VEGF 165, VEGF 183 and VEGF 189), VEGFR-1 and VEGFR-2, was investigated in biopsies from the right atrium and left internal mammary artery (LIMA) of 32 non-diabetic and 20 diabetic patients undergoing coronary artery bypass grafting. Results: Diabetes was independently negatively correlated to total VEGF mRNA expression in atrium. Total VEGF, VEGF 121 and VEGF 165 mRNA levels were upregulated in the LIMA of diabetics vs. non-diabetics. The expression of VEGF receptors in atrium and LIMA was similar between these groups. VEGF 121 and VEGF 165 were the major variants expressed, followed by VEGF 189 and VEGF 183, while VEGF 148 and VEGF 145 were detected in small amounts. The expression profile of VEGF splice variants displayed significant heterogeneity between the examined tissues. Conclusions: This is the first study to quantify VEGF splice variants expression in cardiac and vascular tissue. Our results could help elucidate the role of VEGF splice variants in diabetic complications.

Metabolic syndrome and type 2 diabetes: lipid and physiological consequences

The metabolic syndrome and type 2 diabetes are insulin-resistant states which are commonly associated with an atherogenic dyslipidaemia involving mild to moderately elevated triglycerides, a preponderance of small, dense low-density lipoprotein (LDL) particles and low levels of high-density lipoprotein cholesterol (HDL-C). In addition, there is a spectrum of qualitative changes in the lipoprotein profile, particularly in the functional capacity of HDL to facilitate cellular cholesterol efflux and to protect LDL against oxidative modification. Together, these quantitative and qualitative anomalies promote elevated oxidative stress, endothelial dysfunction and inflammation, which drive the development of premature atherosclerotic cardiovascular disease. Moreover, recent evidence indicates that this dyslipidaemic profile may play a critical role in the development and progression of diabetic microvascular disease. An integrated therapeutic approach to correct both the quantitative and qualitative changes characteristic of diabetic dyslipidaemia clearly constitutes a priority for reduction of both macrovascular and microvascular risk.

Angiogenic Growth Factors in the Treatment of Peripheral Arterial Disease

Peripheral arterial disease (PAD) remains a major cause of morbidity. Despite advances in revascularisation procedures and medical treatment, limb salvage and relief of pain are still not satisfactory in patients with severe disease. This has prompted the exploration of alternative modes of treatment including enhancement of new vessel formation (angiogenesis). Angiogenic Growth Factors (AGF), mainly Vascular Endothelial Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF) and Hepatocyte Growth Factor (HGF) have emerged as exciting therapeutic modalities. Both experimental and clinical studies have demonstrated that topical (mainly intramuscular) AGF gene therapy results in improved peripheral vasculature and alleviation of symptoms. However, most clinical work is limited to small patient series and the long-term safety and efficacy are still unclear. Clinical benefit must be balanced against potential untoward effects, such as tumour growth and atherosclerotic plaque angiogenesis leading to plaque instability. VEGF is important in the pathogenesis of diabetic microvascular disease. Further studies are required before implementation of AGF therapy in clinical practice.

Protein kinase C inhibition in diabetic retinopathy and microvascular disease

AbstractProtein kinase C (PKC) activation by hyperglycaemia may play an important role in the evolution of diabetic retinopathy and other microvascular complications. The PKC‐β inhibitor ruboxistaurin belongs to a new class of drugs and has been studied in several clinical trials in microvascular disease, the outcomes of which are described in this review. Ruboxistaurin exhibits promise as the first oral treatment shown to reduce visual loss and the need for laser treatment for macular oedema in patients with moderate to severe non‐proliferative diabetic retinopathy. Copyright © 2007 John Wiley & Sons.

Role of diabetic microvascular disease in the development of foot wounds

The influence of microvascular changes in diabetic foot tissue breakdown is not fully known. Research on the role of vascular mediators in diabetes and their effect on the microvasculature may help to create a more unified theory.

Retinopathy Predicts Cardiovascular Mortality in Type 2 Diabetic Men and Women

To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences. Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality. Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy. Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.

The Association of Aldose Reductase Gene Polymorphisms with Neuropathy in Patients with Type 2 Diabetes

Background: Previous studies have suggested that polymorphisms in and around the aldose reductase (AR) gene are associated with the development of diabetic microvascular disease. This study explored the hypothesis that the polymorphisms of the (A-C)n dinucleotide repeat sequence, located at 2.1 kilobase (kb) upstream of the transcription start site of AR gene, modulate the risk of diabetic neuropathy (DN).Methods: 66 patients with DN, 30 without microvascular complications (MC) after 20 years of diabetes, and 87 normal healthy controls were studied. To test highly polymorphic microsatellite marker 2.1 kb upstream of the initiation site of the AR gene, we performed polymerase chain reaction using the primer labeled with fluorescent dye and GeneScan by ABI prism 377 automated DNA sequencer and ABI Genotyper software 2.0. Results: Seven alleles (Z-6, Z-4, Z-2, Z, Z+2, Z+4 and Z+6) were identified. Z-2 allele was more frequently observed in patients with DN (77.3%) than in those without MC (43.3%, P = 0.007). The subgroup of patients who developed DN within 5 years after the diagnosis of diabetes also had higher frequency of Z-2 allele (91.7%) compared to those without MC (43.3%, P = 0.028). On the contrary, Z+6 allele tended to be more frequent in patients without MC (10.0%) than in those with DN (0%, P = 0.063). Conclusion: These results support the hypothesis that environmental-genetic interactions may modulate the risk of neuropathy in patients with diabetes. Particularly, the Z-2 allele, in the presence of diabetes, may be associated with the development of DN. (J Kor Diabetes Assoc 31:274~283, 2007)

A Therapeutic Target for Microvascular Complications in Diabetes: Endothelium- Derived Hyperpolarizing Factor

Vascular alterations in diabetes cause or contribute to the etiology of microvascular complications such as nephropathy, neuropathy, and retinopathy. The endothelium controls the vascular smooth muscle tone through the production of vasodilator mediators such as nitric oxide, prostacyclin, and a still-elusive endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is a prominent vasodilator, particularly in smaller arteries, little attention has been paid to the potential role of EDHF responses in diabetes. EDHF function may involve the participation of mediators, including several diffusible factors and non-diffusible factors, (e.g., conduction of hyperpolarization via myoendothelial gap junctions). Indeed, in several vessels, cyclic adenosine 3,5-monophosphate (cAMP) facilitates EDHF responses by enhancing electrotonic conduction via gap junctions. It has been demonstrated that the alterations in EDHF relaxation seen in mesenteric arteries from diabetic rats may be attributable to an increase in phosphodiesterase3 (PDE3) activity, leading to a reduction in the action of cAMP, and moreover the activity of protein kinase A (PKA) is decreased in such arteries. Although an improvement in EDHF responses has not been, as yet, the subject of any direct pharmaceutical effort, increasing cAMP/PKA signaling (e.g., by inhibiting PDE3 activity) has potential as an interesting therapeutic target in diabetic microvascular disease.

John Arthur Luetscher, Jr (1913–2005)

Dr John Luetscher was born in Baltimore, Md, the son of a practicing physician. After attending Princeton University, he entered Johns Hopkins Medical School to follow his father’s footsteps as a physician. He was attracted to the intellectual stimulation and challenge of academic medicine by the Hopkins environment and pursued a research fellowship in physical chemistry at Harvard University after completing his internship. During his fellowship, he was exposed to the rigorous and critical approach to science that was to characterize his entire scientific career. His fellowship work focused on plasma proteins and their participation in salt and water metabolism. He returned to Hopkins to complete his clinical training and in 1942 was offered a faculty position in the Department of Medicine there. In 1948, he left Hopkins to become Associate Professor of Medicine at the fledgling Stanford University Medical School, based at that time in San Francisco, where he joined Dr Thomas Addis, a well-known expert in renal disease. John’s interest in salt and water metabolism was enhanced by the discovery of an adrenal principle, “electrocortin,” which had been shown to influence sodium and potassium excretion. This steroid subsequently was named aldosterone, and John, in conjunction with his research associates, Quentin “Chip” Deming and Ben Johnson, was able to isolate aldosterone from the urine of humans with nephrotic syndrome and congestive heart failure.1,2 He is acknowledged to share the identification of aldosterone with the Taits, Jim and Sylvia Simpson, with whom he also shared the prestigious CIBA (now Novartis) Award of the American Heart Association Council for High …

Does Elevated Arginase Activity Contribute to Diabetes‐induced Endothelial Dysfunction?

L-Arginine (L-Arg) is not only the substrate for nitric oxide synthase (NOS) to produce NO, but also for arginase, which catalyzes L-arg conversion to ornithine and urea. In diabetes, increased arginase activity has been reported and suggested to contribute to endothelial dysfunction by decreasing L-arg availability to NOS. We are investigating this by studies in rats rendered diabetic with streptozotocin and aortic endothelial cells treated with peroxynitrite (ONOO−). Our studies have shown that diabetes causes decreases in plasma levels of NO, increased lipid peroxidation and impaired aortic vasorelaxation that are correlated with increases in arginase activity in both aorta and liver (97% and 233% above control levels, respectively). Concurrent treatment of the diabetic rats with simvastatin (5 mg/kg/day, s.c.) blunted these effects. To determine the impact of oxidative stress on arginase activity, aortic endothelial cells (EC) were treated with ONOO− (25–200 μM), which is known to increase during diabetic microvascular disease. The ECs treated with ONOO− showed a time and dose-dependent increase in arginase activity with a peak effect (110% increase over controls) after 6h with 25 μM ONOO−. Our results suggest that in diabetes increased arginase activity contributes to reduced L-Arg availability for NOS and vascular EC dysfunction. The elevated arginase activity in peroxynitrite-treated ECs suggests that oxidative stress has a key role in the pathological process. Statin treatment has been used to improve NOS function however it also reduced arginase activity in our study. Supplemental L-Arg as therapy for vascular dysfunction may not be effective under conditions of elevated arginase activity, which competes with NOS for the same substrate.

Serum Lipids and the Progression of Nephropathy in Type 1 Diabetes

Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8-9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. In patients with normoalbuminuria (n = 66), progression was associated with male sex (P < 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P < 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (>3 ml x min(-1) x year(-1)) was independently associated with poor glycemic control, hypertension, and LDL size (P < 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P < 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.

Reactive Carbonyls and Polyunsaturated Fatty Acids Produce a Hydroxyl Radical-like Species: A POTENTIAL PATHWAY FOR OXIDATIVE DAMAGE OF RETINAL PROTEINS IN DIABETES

The pattern of oxidized amino acids in aortic proteins of nonhuman primates suggests that a species resembling hydroxyl radical damages proteins when blood glucose levels are high. However, recent studies argue strongly against a generalized increase in diabetic oxidative stress, which might instead be confined to the vascular wall. Here, we describe a pathway for glucose-stimulated protein oxidation and provide evidence of its complicity in diabetic microvascular disease. Low density lipoprotein incubated with pathophysiological concentrations of glucose became selectively enriched in ortho-tyrosine and meta-tyrosine, implicating a hydroxyl radical-like species in protein damage. Model system studies demonstrated that the reaction pathway requires both a reactive carbonyl group and a polyunsaturated fatty acid, involves lipid peroxidation, and is blocked by the carbonyl scavenger aminoguanidine. To explore the physiological relevance of the pathway, we used mass spectrometry and high pressure liquid chromatography to quantify oxidation products in control and hyperglycemic rats. Hyperglycemia raised levels of ortho-tyrosine, meta-tyrosine, and oxygenated lipids in the retina, a tissue rich in polyunsaturated fatty acids. Rats that received aminoguanidine did not show this increase in protein and lipid oxidation. In contrast, rats with diet-induced hyperlipidemia in the absence of hyperglycemia failed to exhibit increased protein and lipid oxidation products in the retina. Our observations suggest that generation of a hydroxyl radical-like species by a carbonyl/polyunsaturated fatty acid pathway might promote localized oxidative stress in tissues vulnerable to diabetic damage. This raises the possibility that antioxidant therapies that specifically inhibit the pathway might delay the vascular complications of diabetes.

Manifestations of Cutaneous Diabetic Microangiopathy

The etiologies of a variety of skin conditions associated with diabetes have not been fully explained. One possible etiological factor is diabetic microangiopathy, which is known to affect the eyes and kidneys in patients with diabetes. There are many mechanisms by which diabetes may cause microangiopathy. These include excess sorbitol formation, increased glycation end products, oxidative damage, and protein kinase C overactivity. All of these processes occur in the skin, and the existence of a cutaneous diabetic microangiopathy has been well demonstrated. These microangiopathic changes are associated with abnormalities of skin perfusion. Because the skin plays a thermoregulatory role, there is significant capillary redundancy in normal skin. In diabetic patients, loss of capillaries is associated with a decrease in perfusion reserve. This lost reserve is demonstrable under stressed conditions, such as thermal stimulation. The associated failure of microvascular perfusion to meet the requirements of skin metabolism may result in diverse skin lesions in patients with diabetes. Many skin conditions peculiar to diabetes are fairly rare. Necrobiosis lipoidica diabeticorum (NLD) and diabetic bullae occur very infrequently as compared with diabetic retinopathy and nephropathy. Conversely, there is a correlation between diabetic microvascular disease and NLD. This correlation also exists with more common skin conditions, such as diabetic dermopathy. This relationship suggests that diabetic microangiopathy may contribute to these conditions even if it is not primarily causal. Clinically, the major significance of diabetic cutaneous microangiopathy is seen in skin ulceration which is very common and has a major impact on diabetic patients. Many factors contribute to the development of diabetic foot ulcers. Neuropathy, decreased large vessel perfusion, increased susceptibility to infection, and altered biomechanics all play a role, but there is no doubt that inadequate small blood vessel perfusion is a major cause of the inability to heal small wounds that eventually results in ulcer formation. The accessibility of skin capillaries makes cutaneous diabetic microangiopathy an attractive model for research on the evolution of microvascular disease in diabetic patients.

Diabetes mellitus and optic atrophy: a study of Wolfram syndrome in the Lebanese population.

Wolfram syndrome (WFS) is a rare hereditary neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). WFS seems to be a heterogeneous disease that has not yet been fully characterized in terms of clinical features and pathophysiological mechanisms because the number of patients in most series was small. In this study we describe 31 Lebanese WFS patients belonging to 17 families; this, to our knowledge, is the largest number of patients reported in one series so far. Criteria for diagnosis of WFS were the presence of insulin-dependent diabetes mellitus and optic atrophy unexplained by any other disease. Central diabetes insipidus was found in 87% of the patients, and sensorineural deafness confirmed by audiograms was present in 64.5%. Other less frequent features included neurological and psychiatric abnormalities, urodynamic abnormalities, limited joint motility, cardiovascular and gastrointestinal autonomic neuropathy, hypergonadotropic hypogonadism in males, and diabetic microvascular disease. New features, not reported in previous descriptions, such as heart malformations and anterior pituitary dysfunction, were recognized in some of the patients and participated in the morbidity and mortality of the disease. Genetic analysis revealed WFS1 gene mutations in three families (23.5%), whereas no abnormalities were detected in mitochondrial DNA. In conclusion, WFS is a devastating disease for the patients and their families. More information about WFS will lead to a better understanding of this disease and hopefully to improvement in means of its prevention and treatment.

The tissue renin-angiotensin-aldosterone system in diabetes mellitus.

Diabetes is associated with an inordinate burden of cardiovascular and renal disease, which is expected to accelerate during the next few decades. The relationship between the renin-angiotensin system (RAS) and diabetic macrovascular and microvascular disease is well established. The contribution of the tissue RAS in disease pathogenesis has recently been the focus of much interest, and has prompted investigators to explore the use of high-dose RAS inhibition with monotherapy or combination therapy to provide a more complete blockade of the actions of angiotensin II, beyond lowering blood pressure. There is now evidence to support this approach to maximize cardiovascular and renal protection. Optimal dosing strategies remain uncertain, but tissue specificity does not appear to be important if the doses of angiotensin-converting enzyme-I and angiotensin-receptor binders are high enough. The purpose of this review is to highlight our current understanding of the role of the tissue RAS in the pathogenesis of diabetic end-organ damage and ongoing strategies to interfere pharmacologically.

The role of lipids in the development of diabetic microvascular complications: implications for therapy.

Dyslipidemia is a major factor responsible for coronary heart disease and its reduction decreases coronary risk in patients with diabetes mellitus. However, the association of dyslipidemia with microvascular complications and the effect of intervention with lipid-lowering therapy in diabetes have been less investigated. We present the systematic review of association and intervention studies pertaining to dyslipidemia and microvascular disease in diabetes and also review possible mechanisms. Dyslipidemia may cause or exacerbate diabetic retinopathy and nephropathy by alterations in the coagulation-fibrinolytic system, changes in membrane permeability, damage to endothelial cells and increased atherosclerosis. Hyperlipidemia is associated with faster decline in glomerular filtration rate and progression of albuminuria and nephropathy. Recent evidence also suggests a role of lipoprotein(a) in progression of retinopathy and nephropathy in patients with diabetes mellitus. Lipid-lowering therapy, using single agents or a combination of drugs may significantly benefit diabetic retinopathy and diabetic nephropathy. In particular, hydroxymethyl glutaryl coenzyme A reductase inhibitors may be effective in preventing or retarding the progression of microvascular complications because of their powerful lipid-lowering effects and other additional mechanisms. However, most of the data are based on short-term studies, and need to be ascertained in long-term studies. Until more specific guidelines are available, aggressive management of diabetic dyslipidemia, according to currently accepted guidelines, should be continued for the prevention of macrovascular disease which would also benefit microvascular complications.

The Renin-Angiotensin System Influences Ocular Endothelial Cell Proliferation in Diabetes: Transgenic and Interventional Studies

Neovascularization in the retina and iris of diabetic patients is a major cause of severe visual loss. However, study of these lesions is compromised by the lack of a comparable diabetic rodent model. Because the vasoactive and angiogenic agent, angiotensin II, is involved in diabetic microvascular disease, we aimed to determine whether endothelial cell proliferation could be induced in the retinae and irides of hypertensive transgenic (mRen-2)27 rats that display an enhanced extra-renal renin-angiotensin system (RAS), including the eye. Six-week-old Ren-2, spontaneously hypertensive, and Sprague-Dawley rats received either streptozotocin or control vehicle and were studied for 36 weeks. Additional nondiabetic and diabetic Ren-2 rats were treated throughout with the angiotensin-converting enzyme inhibitor lisinopril (LIS) (10 mg/kg/day in drinking water). Endothelial cell proliferation was only observed in retinae and irides of diabetic Ren-2 rats and was reduced with LIS. In diabetic Ren-2, vascular endothelial growth factor (VEGF) and VEGFR-2 mRNA were increased in retinae and irides and reduced with LIS. Diabetes activated ocular renin in Ren-2 but not Sprague-Dawley rats. The diabetic Ren-2 rat is a model of intraocular endothelial cell proliferation that can be attenuated by RAS blockade via VEGF-dependent pathways. RAS blockade is a potential treatment for vision-threatening diabetic microvascular complications.

Brachial-ankle pulse wave velocity is useful for evaluation of complications in type 2 diabetic patients.

Pulse wave velocity (PWV) is useful for the evaluation of aortic stiffness. The brachial-ankle PWV (baPWV) and carotid PWV (from heart to carotid) were compared to study the relation of these two types of PWVs to diabetic complications in patients with type 2 diabetes mellitus. The baPWV was determined by oscillometrically measuring the pulse volume record at the upper arm and ankles. The carotid PWV was measured tonometrically. Ninety patients with type 2 diabetes mellitus were divided into tertile groups on the basis of baPWV or carotid PWV. The correlations of these variables with albuminuria, peripheral neuropathy, coefficient of variation of R-R intervals (CV R-R) on the electrocardiogram at rest, and retinopathy were examined by logistic regression analysis. After adjustment for age, systolic blood pressure, and duration of diabetes, logistic regression analysis showed that baPWV was directly related to the frequencies of albuminuria, decreased CV R-R, peripheral neuropathy, and retinopathy. In contrast, carotid PWV did not significantly correlate with any diabetic complications. We conclude that oscillometrically determined baPWV is related to the risk of diabetic microvascular disease in patients with type 2 diabetes mellitus and suggested to be useful for assessing risk factors of diabetic complications.