Diabetic Microvascular Disease Research Articles

Benefits and Risks for Intensive Glycemic Control in Patients With Diabetes Mellitus

Overweight, obesity, pre-diabetes and diabetes have become epidemic in most of Western society. An estimated 25.8 million United States adults have diabetes and some 79 million have prediabetes and are thus at high risk for future development of diabetes. Appropriate treatment of the ABCs of diabetes [A1C, blood pressure and cholesterol (dyslipidemia)] can reduce the risk for the development and progression of diabetic complications. This paper reviews some of the research studies that support treatment goals established by the American Association of Clinical Endocrinologists/American College of Endocrinology and the American Diabetes Association. Multiple studies have demonstrated that intensive glycemic control will reduce the risk for diabetes microvascular and neuropathic disease, but none showed decreased macrovascular disease events during the initial phase of the trials, although benefit was seen in long-term follow-up of the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study. The American Association of Clinical Endocrinologists/American College of Endocrinology and the American Diabetes Association goals for glycemia informed by these studies indicate the importance of individualizing targets for patients based on factors including the duration of diabetes, presence of acute and chronic complications and life expectancy. Writing groups convened by these organizations have also developed treatment algorithms to help clinicians appropriately use both lifestyle and pharmacotherapy interventions to safely achieve glycemic targets.

Contribution of sex hormones in the progression of diabetic microvascular diseases.

Contribution of sex hormones in the progression of diabetic microvascular diseases.

Galectin-3 Protein Modulates Cell Surface Expression and Activation of Vascular Endothelial Growth Factor Receptor 2 in Human Endothelial Cells

Angiogenesis is heavily influenced by VEGF-A and its family of receptors, particularly VEGF receptor 2 (VEGF-R2). Like most cell surface proteins, VEGF-R2 is glycosylated, although the function of VEGF-R2 with respect to its glycosylation pattern is poorly characterized. Galectin-3, a glycan binding protein, interacts with the EGF and TGFβ receptors, retaining them on the plasma membrane and altering their signal transduction. Because VEGF-R2 is glycosylated and both galectin-3 and VEGF-R2 are involved with angiogenesis, we hypothesized that galectin-3 binds VEGF-R2 and modulates its signal transduction as well. Employing a Western blot analysis approach, we found that galectin-3 induces phosphorylation of VEGF-R2 in endothelial cells. Knockdown of galectin-3 and Mgat5, an enzyme that synthesizes high-affinity glycan ligands of galectin-3, reduced VEGF-A mediated angiogenesis in vitro. A direct interaction on the plasma membrane was detected between galectin-3 and VEGF-R2, and this interaction was dependent on the expression of Mgat5. Using immunofluorescence and cell surface labeling, we found an increase in the level of internalized VEGF-R2 in both Mgat5 and galectin-3 knockdown cells, suggesting that galectin-3 retains the receptor on the plasma membrane. Finally, we observed reduced suture-induced neovascularization in the corneas of Gal3(-/-) and Mgat5(-/-) mice. These findings are consistent with the hypothesis that, like its role with the EGF and TGFβ receptors, galectin-3 contributes to the plasma membrane retention and proangiogenic function of VEGF-R2.

Is cognitive impairment the fourth diabetic microvascular complication?

Is cognitive impairment the fourth diabetic microvascular complication?

Statins for prevention of diabetic-related blindness: a new treatment option?

Diabetic retinopathy (DR), the most feared complication of diabetes, compromises vision and quality of life of approximately 50 million people worldwide, with its prevalence projected to double by 2025 [101]. DR, the leading cause of blindness in working-age adults in the USA, is characterized by early neurodegeneration, glial activation and vascular injury, which includes breakdown of the blood–retina barrier (BRB) and acellular capillary formation that eventually leads to retinal neo-vascularization and blindness (reviewed in [1]). Interestingly, early clinical trials including the Hoorn study, the Early Treatment Diabetic Retinopathy Study (ETDRS), and the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) [2–4] indicated that elevated serum lipids, including total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol, were associated with the presence of hard exudates and increased risk of DR. These results suggested that lipid-lowering therapies might be beneficial in the reduction of hard exudates and the associated vision loss in patients with DR. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that lower total and LDL-cholesterol in diabetic patients with or without cardiovascular disease. They inhibit the generation of mevalonate, a precursor of cholesterol, and inhibit isoprenoid synthesis. The beneficial effects of statins may extend beyond their cholesterol-lowering effects, to so-called pleiotropic effects, which include improving endothelial function, attenuating vascular and myocardial remodeling, inhibiting vascular inflammation and oxidation, and stabilizing atherosclerotic plaques. Statins’ pleiotropic effects are mainly attributed to blocking the isoprenylation of small GTPase proteins such as Rac-1, Rho and Cdc42 (reviewed in [5]). Although statins have reported benefits in diabetic microvascular diseases, their efficacy for DR has not been thoroughly investigated [6–8].

Association of retinal arteriolar dilatation with lower verbal memory: the Edinburgh Type 2 Diabetes Study

Retinal vascular calibre changes may reflect early subclinical microvascular disease in diabetes. Because of the considerable homology between retinal and cerebral microcirculation, we examined whether retinal vascular calibre, as a proxy of cerebral microvascular disease, was associated with cognitive function in older people with type 2 diabetes. A cross-sectional analysis of 954 people aged 60-75 years with type 2 diabetes from the population-based Edinburgh Type 2 Diabetes Study was performed. Participants underwent standard seven-field binocular digital retinal photography and a battery of seven cognitive function tests. The Mill Hill Vocabulary Scale was used to estimate pre-morbid cognitive ability. Retinal vascular calibre was measured from an image field with the optic disc in the centre using a validated computer-based program. After age and sex adjustment, larger retinal arteriolar and venular calibres were significantly associated with lower scores for the Wechsler Logical Memory test, with standardised regression coefficients -0.119 and -0.084, respectively (p < 0.01), but not with other cognitive tests. There was a significant interaction between sex and retinal vascular calibre for logical memory. In male participants, the association of increased retinal arteriolar calibre with logical memory persisted (p < 0.05) when further adjusted for vocabulary, venular calibre, depression, cardiovascular risk factors and macrovascular disease. In female participants, this association was weaker and not significant. Retinal arteriolar dilatation was associated with poorer memory, independent of estimated prior cognitive ability in older men with type 2 diabetes. The sex interaction with stronger findings in men requires confirmation. Nevertheless, these data suggest that impaired cerebral arteriolar autoregulation in smooth muscle cells, leading to arteriolar dilatation, may be a possible pathogenic mechanism in verbal declarative memory decrements in people with diabetes.

High-risk diabetic nephropathy patients: The outcome of evidence-based clinical practice in an outpatient clinic

Objective A retrospective audit to assess the impact of a combined diabetes–renal consultant clinic over 10 years, on slowing the progression of diabetic nephropathy, using recognised markers of renal disease progression, including creatinine clearance and proteinuria. Methods 44 high-risk patients with diabetic nephropathy defined as having significant proteinuria (an elevated albumin creatinine ratio greater than 30 mg/mmol), and hypertension, a progressive rise in plasma creatinine or other evidence of diabetic microvascular disease or macrovascular disease, were identified. Sufficient follow up was defined as at least two data sets over a 12-month period prior to referral to the combined clinic, and at least 18 months of combined clinic follow up thereafter. Results In this high risk group, GFR was falling at an average of 7.97 m/min/year (95% CI 9.83–6.10 ml/min/year) at the time of referral and following clinic intervention this was significantly reduced to 3.17 ml/min/year (95% CI 4.47–1.87 ml/min/year) over the duration of follow up. Blood pressure, glycaemic control and lipid status remained stable and close to current recommended guidelines. Conclusions A combined diabetes–renal consultant clinic is an effective intervention to improve the outcome of high-risk diabetics with progressive diabetic nephropathy.

Screening Tests for Renal Impairment in Patients with Type 2 Diabetes: The what, when, and how

The global course of obesity and diabetes presents an alarming forecast for the near future. As the prevalence rates continue to increase and the afflicted population grows younger in age, the associated complications of diabetes will come to pose a greater strain on patients, society, and national health care systems. In recent years, a number of studies have demonstrated the clinical benefits of strict diabetes control in the prevention of debilitating complications, including retinal, renal, and cardiovascular disease. These data highlight the need to maximize our efforts in diabetes prevention and early disease management. Renal dysfunction is a surrogate marker of diabetic microvascular disease, and thus early recognition of renal impairment in patients with diabetes provides an opportunity to modify treatment strategy and improve long-term disease outcomes. This review will summarize methods of assessing renal function and the most recent guidelines for the early screening and diagnosis of diabetic kidney disease.

Significance of three kinds of microparticle levels in diabetic angiopathy

Objective To investigate the levels of mieropartieles originated from platelet (PMP),endothelium (EMP),and tissue factor-bearing microparticles (TF+ MP) in diabetes mellitus and to analyze its relationship with diabetic angiopathy.Methods PMP,EMP or TF+ MP were measured in 106 cases of diabetes mellitus and 50 controls by flow eytometry.The differences of EMP between groups of diabetic macrovascular disease and diabetic microvascular disease were determined.Results The levels of EMP in diabetic patients were higher than that in the control(164.20±128.88 vs 63.81±40.84,P<0.05).Diabetic cases with complication showed higher expression level of EMP than those without complications(184.12±152.77,188.21±149.55 vs 138.53±99.87,both P<0.05).However,no distinct increase was observed in PMP and TF+ MP level in diabetes groups compared with control group.Conclusions Endothelial dysfunction,may contribute to the increased level of EMP in patients with diabetes,especially those complicated with vascular diseases.EMP level may be used to evaluate the status of endothelial function and the development of diabetic angiopathy. Key words: Diabetes mellitus; Angiopathy; Microparticles; Endothelial dysfunction

PPARα: an emerging therapeutic target in diabetic microvascular damage

The global pandemic of diabetes mellitus portends an alarming rise in the prevalence of microvascular complications, despite advanced therapies for hyperglycemia, hypertension and dyslipidemia. Peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in organs affected by diabetic microvascular disease (retina, kidney and nerves), and its expression is regulated specifically in these tissues. Experimental evidence suggests that PPARalpha activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications. PPARalpha has emerged as a novel target to prevent microvascular disease, via both its lipid-related and lipid-unrelated actions. Despite strong experimental evidence of the potential benefits of PPARalpha agonists in the prevention of vascular damage, the evidence from clinical studies in patients with diabetes mellitus remains limited. Promising findings from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study on microvascular outcomes are countered by elevations in participants' homocysteine and creatinine levels that might potentially attenuate the benefits of PPARalpha activation. This Review focuses on the role of PPARalpha activation in diabetic microvascular disease and highlights the available experimental and clinical evidence from studies of PPARalpha agonists.

DUAL INHIBITION OF CLASSICAL PKC-ALPHA AND PKC-BETA-ISOFORMS IN A PHARMACOLOGICAL AND DOUBLE KNOCK-OUT MOUSE APPROACH LEADS TO PROTECTION AGAINST DIABETIC NEPHROPATHY: 5A.04

Both classical PKC isoforms, PKC-α and -β, have been implicated in the pathogenesis of diabetic microvascular diseases. We previously elucidated the specific role of these individual isoforms and revealed that activation of the PKC-β-isoform contributes to high-glucose-induced renal fibrosis whereas perlecan as well as nephrin and VEGF expression are regulated by a PKC-α-isoform-dependent signaling pathway leading to diabetic albuminuria. We now tested the hypothesis if deletion of both classical PKC isoforms is able to completely abolish the development of diabetic nephropathy in the streptozotocin-induced diabetic mouse model. We therefore studied distinct pharmacological approaches while inhibiting both classical PKC isoforms and validated the phenotype of nondiabetic and streptozotocin-induced diabetic homozygeous PKC-α/β double knock-out mice (PKC-α/β-/-) compared to appropriate 129/SV wild type mice. After 8 weeks of diabetes mellitus the high-glucose-induced renal and glomerular hypertrophy as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin was abolished in the PKC-α/β-/- mice compared to WT controls. Furthermore, the high-glucose-induced expression of the profibrotic cytokine TGF-â1 was significantly diminished in the PKC-α/β-/- mice in comparison to diabetic WT mice. The loss of the basal membrane proteoglycan perlecan and the podocyte protein nephrin is prevented in the diabetic state in the PKC-α/β-/- mice. Furthermore, we were able to demonstrate, that a PKC-α/β inhibitor had a similar effect. In summary, blockade of the two prominent PKC isoforms α and β are able to prevent early diabetic nephropathy while inhibiting prosclerotic glomerular and tubulo-interstitial changes as well as the development of albuminuria. These results demonstrate that downregulation of the dual PKC-isoform activation in the diabetic state in vivo is a suitable therapeutic target in the prevention of diabetic microvascular complications such as diabetic nephropathy.

Prorenin, Renin, and Their Receptor

In addition to its well-known role in regulating blood pressure and fluid balance, the renin-angiotensin-aldosterone system (RAAS) has continued to fascinate both researchers and clinicians because of the several additional functions that it has been proposed to carry out. Disruption of the production or action of angiotensin II (Ang II) during development, either by gene mutation or by pharmacological blockade, results in tubular agenesis and anemia in the fetus (humans) or offspring (laboratory animals) and is most often lethal.1,2 Some of the suspected, but still unproven, roles of angiotensin peptides include effects on energy metabolism,3 longevity,4 memory,5 autoimmune diseases,6,7 and a direct, blood pressure-independent effect on tissue damage. This latter role is extremely hard to prove, because the effects of Ang II on blood pressure are hard to separate from its potential direct effects on tissues both in the laboratory and in clinical trials. The most recent developments in RAAS research have led to the suggestion that tissue damage may not be solely attributable to the action of angiotensin peptides but may also involve a direct effect of renin and its protein precursor, prorenin. The concept that prorenin and renin play a direct role in vascular pathologies is largely built on 4 lines of evidence. First is the finding that elevations of circulating prorenin were associated (and may even precede) diabetic microvascular disease.8,9 Second is the report that transgenic rats engineered to have a 400-fold increase in circulating prorenin developed severe cardiac remodeling and renal lesions in the absence of hypertension,10 raising the possibility that prorenin was not only associated with tissue damage but that it may even be responsible for the damage by a mechanism that did not require Ang II generation. Third is the discovery of the so-called (pro)renin receptor ((P)RR), …

Review of the Relationship between Renal and Retinal Microangiopathy in Diabetes Mellitus Patients

Diabetes mellitus is a group of metabolic disorders of carbohydrate metabolism in which glucose is underutilized, producing hyperglycemia. The latter complications of diabetes mellitus include microvascular complications the major microvascular complications, retinopathy and nephropathy, are the more important causes of blindness and end-stage renal disease in Europe. Different risk factors such as diabetes duration, blood pressure and lipid control have consistently been shown to correlate with both microvascular complications for diabetes. Despite the efforts of studies to correlate the two major diabetes mellitus microvascular complications, retinopathy and nephropathy, the relationship has not so far been clearly described. However, the currently literature data suggest that the presence of a pre-existing microvascular complication (retinopathy or nephropathy) may contribute to the development of another, especially in DM1 patients. More prospective studies are needed if we are to know the exact mechanism of how these diabetic microvascular diseases correlate, and if we are to develop a scoring system for predicting the development of those complications that will allow us to identify the patients at risk, with its consequent positive impact on patients' quality of life. The aim of the present study is to review the literature on the diagnosis, epidemiology, pathology, and risk factors in diabetic nephropathy and retinopathy, and then a revision of the possible relation between renal and retinal diabetic microangiopathy.

The association of plasma fibrinogen concentration with diabetic microvascular complications in young adults with early-onset of type 2 diabetes

Aims Diabetic nephropathy is an important risk factor for cardiovascular diseases (CVD). The underlying etiology is not fully understood but may be related to changes in inflammatory and hemostatic markers with kidney disease. We investigated the associations of the markers with microvascular complications in Pima Indians (PI) with early-onset type 2 diabetes (T2DM). Methods C-reactive protein, interleukine-6, fibrinogen, D-dimer, plasmin–antiplasmin complex and plasminogen activator inhibitor-1 were measured in 104 PI (age: 32 ± 4y) with diabetes and 59 (32 ± 4y) with fasting glucose <110 mg/dl and 2-h glucose <140 mg/dl. Urine albumin to creatinine ratio (ACR) was used as marker of nephropathy. Severity of retinopathy was classified in the worse eye by direct ophthalmoscopy as none, background and proliferative. Results Of these markers, only fibrinogen was associated with ACR ( r = 0.25, p < 0.01). After adjustment for age, sex, percentage Pima heritage, smoking status, diabetes duration, blood pressure and use of aspirin, antihypertensive and antihyperglycemic agents, general linear models (with natural log-transformed values of fibrinogen and ACR as dependent and independent variables, respectively) revealed that a one percent increase in ACR would yield a 0.02% increase in the fibrinogen ( β = 0.02, p < 0.05). Plasma fibrinogen was also significantly increased with severity of diabetic retinopathy ( p < 0.05). Conclusions Increased plasma fibrinogen concentration was associated with diabetic microvascular disease, in particular with nephropathy. This may help to explain the etiologic link between nephropathy and CVD.

The Role of Inflammatory Cytokines in Diabetes and Its Complications

The prevalence of diabetes worldwide is increasing rapidly in association with the increase in obesity. Complications are a major fear of patients with diabetes. Complications of diabetes affect many tissues and organs, causing retinopathy, nephropathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, stroke, and periodontal pathologies. Immunologic abnormalities are associated with type 1 and type 2 diabetes and diabetic complications. T cell abnormalities are believed to be the major cause of autoimmune disease in type 1 diabetes, leading to the destruction of pancreatic islets. In type 2 diabetes, inflammation and activation of monocytes are postulated to be important for enhancing insulin resistance and may contribute to the loss of insulin secretory function by islet cells. Many factors can enhance insulin resistance, including genetics, a sedentary lifestyle, obesity, and other conditions, such as chronic inflammation or infection. Increases in inflammation, such as activation of monocytes and increased levels of inflammatory markers, e.g., C-reactive protein, plasminogen activator inhibitor-1, and other cytokines, were reported in insulin-resistant states without diabetes. One possible mechanism is that abnormal levels of metabolites, such as lipids, fatty acids, and various cytokines from the adipose tissue, activate monocytes and increase the secretion of inflammatory cytokines, enhancing insulin resistance. According to this model, obesity activates monocytes and enhances insulin resistance, increasing the risk for type 2 diabetes. Abnormalities in innate immunity might also participate in the development of diabetic complications. In general, hyperglycemia is the main initiator of diabetic retinopathy, nephropathy, and neuropathy, and it participates in the development of diabetic cardiovascular diseases. Although the precise role of inflammation in the development of diabetic microvascular diseases is still unclear, it is likely that inflammation induced by diabetes and insulin resistance can accelerate atherosclerosis in patients with diabetes. Also, it was shown that conditions with an inflammatory basis, such as obesity and type 2 diabetes, can contribute to periodontal disease, suggesting that periodontal abnormalities may be partly influenced by inflammatory changes. Further research is required to confirm the role of inflammation and the onset of diabetes, microvascular diseases, and periodontal pathologies.

Anti-endothelial cell antibodies in insulin-dependent diabetes mellitus.

The prevalence of IgG class antibodies to endothelial cells (AECA) was studied in 136 young patients with insulin-dependent diabetes mellitus by an enzyme immunoassay using human umbilical cord vein endothelial cells. The patients were divided into four groups according to the time between diagnosis and study and their results were compared with those in control children and blood donors. AECA became progressively more frequent with the duration of diabetes, being 4% in diabetics tested within 2 weeks of diagnosis and reaching 34% after an average disease duration of 11.2 years. They were not more common in patients with neuropathy, retinopathy or nephropathy than in patients without these complications, but were associated with co-existing thyroid disease and IgA deficiency. The results suggest that in insulin-dependent diabetes mellitus AECA are associated with co-existing autoimmune disorders but not with diabetic microvascular disease.

Retinal and Cerebral Microvascular Signs and Diabetes

Diabetes increases the risk for microvascular disease. The retina and the brain both have intricate microvascular systems that are developmentally similar. We sought to examine whether microvascular lesions in the retina and in the brain are associated and whether this association differs among people with and without diabetes. The analysis included 4,218 participants of the Icelandic population-based Age, Gene/Environment Susceptibility-Reykjavik Study who were born in 1907-1935 and who were previously followed as a part of the Reykjavik Study. Retinal focal arteriolar narrowing, arteriovenous (AV) nicking, and microaneurysms/hemorrhages were evaluated on digital retinal images of both eyes. Cerebral microbleeds (CMBs) were evaluated from magnetic resonance images. Data were analyzed with logistic and multinomial logistic regression models controlling for demographics, major cardiovascular risk factors, cerebral infarcts, and white matter lesions. Evidence of brain microbleeds was found in 485 (11.5%) people, including 192 with multiple (>or=2) microbleeds. Subjects with signs of retinal microvascular lesions were at a significantly increased likelihood for having multiple CMBs. People with diabetes in combination with the presence of either retinal AV nicking (odds ratio [OR] 2.47 [95% CI 1.42-4.31]) or retinal microaneurysms/hemorrhages (2.28 [1.24-4.18]) were significantly more likely to have multiple CMBs. Retinal microvascular abnormalities and brain microbleeds may occur together in older adults. People with both diabetes and signs of retinal microvascular lesions (AV nicking and microaneurysms/hemorrhages) are more likely to have multiple microbleeds in the brain. Microvascular disease in diabetes extends to the brain.

Bilateral basal ganglia lesions in patients with end‐stage diabetic nephropathy (Brief Communication)

Summary: Acute movement disorder associated with reversible bilateral basal ganglia lesions is an increasingly recognized syndrome in patients with end‐stage renal disease, especially in the setting of concurrent diabetes mellitus. We report an elderly man with end‐stage diabetic nephropathy treated by daily automated peritoneal dialysis who developed subacute symptoms of gait disturbance, dysarthria, dysphagia and lethargy. Computed tomography and magnetic resonance imaging of the head revealed bilateral symmetrical basal ganglia lesions. Repeat imaging 3 weeks later showed that these lesions had regressed spontaneously. However, his neurological symptoms improved slowly. These findings were similar to 23 other cases in the literature. Review of these cases shows that clinical features were predominantly bradykinesia, gait disturbance and concurrent metabolic acidosis (observed in 90% of cases). The pathogenesis of this condition has not been clearly defined, but uraemia may be an aggravating factor in predisposed patients, particularly in the presence of diabetic microvascular disease. There is no specific treatment for this condition; supportive measures are the mainstay of management. In the majority of patients, neurological improvement lags behind regression of basal ganglia lesions seen with neuroimaging, and the long‐term outcome is variable.

Diabetic Kidney Disease: Chronic Kidney Disease and Diabetes

The traditional clinical hallmark of chronic kidney disease (CKD) in diabetic microvascular disease of the kidney has been overt proteinuria; once manifest, diabetic nephropathy was considered apparent. The term “nephropathy” classically was associated with foamy urine, hypertension, and renal edema formation attributable to sodium retention and fostered by impaired kidney function and hyperglycemia. In fact, the simultaneous diagnosis of the triad of proteinuria, high blood pressure, and edema actually indicated that “the horse was out of the barn”; diabetic kidney disease was already present and likely had been for years. To emphasize the impact of diabetes on the renal parenchyma at much earlier stages of the disease, the National Kidney Foundation's Kidney Dialysis Outcomes Quality Initiative Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease now promote the term “diabetic kidney disease” (DKD) as a nonproteinuric designation of CKD in type 1 or type 2 diabetes.1 DKD will occur in 30–40% of people with diabetes, and one-third of these individuals may develop kidney failure. DKD occurs in patients with either type 1 or type 2 diabetes; however, patients with type 2 diabetes often present with a mixed picture of atherosclerotic renal changes coincident with diabetic histological findings. Judgment of whether hypertension or diabetes is the dominant lesion, in the absence of a kidney biopsy, is typically predicated on whether a renal ultrasonogram depicts small or normal-to-large kidneys. In the former instance, hypertensive angiosclerosis is considered causative, whereas the latter circumstance coincides with DKD, irrespective of the level of proteinuria. Importantly, when microalbuminuria, macroalbuminuria, or intermediate levels of protein excretion are detectable, the glomerular filtration rate (GFR) has usually passed through the stage of hyperfiltration. Thus, DKD is already present at a normal or slightly less-than-normal GFR. Principally, kidney function is declining with the GFR. At …

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).