Increased erythrocyte 3-DG and AGEs in diabetic hemodialysis patients: role of the polyol pathway

BACKGROUND: 3-Deoxyglucosone (3-DG) accumulating in uremic serum plays an important role in the formation of advanced glycation end products (AGEs). To determine if 3-DG is involved in the formation of intracellular AGEs, we measured the erythrocyte levels of 3-DG and AGEs such as imidazolone and N epsilon-carboxymethyllysine (CML) in hemodialysis (HD) patients with diabetes. Further, to determine if the polyol pathway is involved in the formation of erythrocyte 3-DG and AGEs, an aldose reductase inhibitor (ARI) was administered to these patients. METHODS: The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were measured in ten diabetic HD patients before and after treatment with ARI (epalrestat) for eight weeks, and were compared with those in eleven healthy subjects. 3-DG was incubated in vitro with hemoglobin for two weeks to determine if imidazolone and CML are formed by reacting 3-DG with hemoglobin. RESULTS: The erythrocyte levels of sorbitol, 3-DG, imidazolone, and CML were significantly elevated in diabetic HD patients as compared with healthy subjects. The erythrocyte levels of 3-DG significantly decreased after HD, but sorbitol, imidazolone or CML did not. The administration of ARI significantly decreased the erythrocyte levels of sorbitol, 3-DG and imidazolone, and tended to decrease the CML level. Imidazolone was rapidly produced in vitro by incubating 3-DG with hemoglobin, and CML was also produced, but less markedly as compared with imidazolone. CONCLUSION: The erythrocyte levels of 3-DG and AGEs are elevated in diabetic HD patients. The administration of ARI reduces the erythrocyte levels of 3-DG and AGEs, especially imidazolone, as well as sorbitol. Thus, 3-DG and AGEs, especially imidazolone, in the erythrocytes are produced mainly via the polyol pathway. ARI may prevent diabetic and uremic complications associated with AGEs.     

Changes in skeletal muscle contractile properties in streptozocin-induced diabetic rats and role of polyol pathway and hypoinsulinemia

Functional changes in slow-twitch soleus and fast-twitch extensor digitorum longus muscles were assessed after 2 mo of streptozocin-induced diabetes in rats. For soleus, there was a slowing of twitch times both for contraction and relaxation and a reduction of maximum tetanic relaxation rate. There was little effect on strength performance assessed by maximal tetanic tension production. Treatment with the aldose reductase inhibitor ponalrestat largely prevented relaxation defects but had little effect on contraction. For the fast muscle, twitch times were relatively unaffected, but maximum tetanic relaxation rate was reduced. In addition, tetanic tension output decreased. These changes were largely prevented by ponalrestat treatment. The effects of partial insulin therapy were also investigated. This regimen reduced hypoinsulinemia, but sufficient hyperglycemia remained to stimulate the polyol pathway. It prevented the slowing of soleus twitch contraction but had no effect on relaxation. For extensor digitorum longus, insulin produced further deleterious effects on tetanic tension and maximum relaxation rate, which were antagonized by ponalrestat. A 1% dietary myo-inositol supplement had little effect on contractile function in slow or fast muscles. It was concluded that polyol-pathway activity is an important factor underlying skeletal muscle functional changes in diabetes, probably acting through disruption of Ca2+ handling. Hypoinsulinemia was considered a secondary factor causing atrophy, particularly of fast muscles. There was no evidence of effects dependent on neuropathy.     

Surgeon's role in diabetic retinopathy

Diabetic retinopathy (DR) is the most frequent cause of blindness during the patient's economically active years. The probability of developing this disease increases with the number of diabetic patients in our country, as well as their survival. In general, DR progression is predictable, from minimum changes (barely detectable through ophthalmoscopy) to advanced damage that requires surgical treatment. However, in Mexico, its late detection frequently necessitates retinal surgery. Current resources regarding vitreous and retinal surgery have improved anatomic results in the treatment of DR. Among the most important of these are panoramic vision systems, high-speed cutting equipment, small-caliber microsurgical instruments, endophotocoagulation, adjuvants such as heavy liquids, silicon oil and angiogenesis inhibitors, which have been the topic of several recent studies.     

A role for the polyol pathway in the early neuroretinal apoptosis and glial changes induced by diabetes in the rat

We tested the hypothesis that the apoptosis of inner retina neurons and increased expression of glial fibrillary acidic protein (GFAP) observed in the rat after a short duration of diabetes are mediated by polyol pathway activity. Rats with 10 weeks of streptozotocin-induced diabetes and GHb levels of 16 +/- 2% (mean +/- SD) showed increased retinal levels of sorbitol and fructose, attenuation of GFAP immunostaining in astrocytes, appearance of prominent GFAP expression in Müller glial cells, and a fourfold increase in the number of apoptotic neurons when compared with nondiabetic rats. The cells undergoing apoptosis were immunoreactive for aldose reductase. Sorbinil, an inhibitor of aldose reductase, prevented all abnormalities. Intensive insulin treatment also prevented most abnormalities, despite reducing GHb only to 12 +/- 1%. Diabetic mice, known to have much lower aldose reductase activity in other tissues when compared with rats, did not accumulate sorbitol and fructose in the retina and were protected from neuronal apoptosis and GFAP changes in the presence of GHb levels of 14 +/- 2%. This work documents discrete cellular consequences of polyol pathway activity in the retina, and it suggests that activation of the pathway and "retinal neuropathy" require severe hyperglycemia and/or high activity of aldose reductase. These findings have implications for how to evaluate the role of the polyol pathway in diabetic retinopathy.     

Evidence for existence of polyol pathway in cultured rat mesangial cells

The accumulation of polyols has been previously found in renal glomeruli isolated from streptozocin-induced diabetic (STZ-D) rats, although the intraglomerular polyol pathway has not been exactly localized. Because we have previously observed mesangial cell dysfunction in STZ-D rats, we examined whether the polyol pathway exists in mesangial cells as a possible candidate of the cause of cellular dysfunction. The activities of two polyol pathway enzymes, aldose reductase and sorbitol dehydrogenase, were clearly detected in the crude homogenate of cultured mesangial cells at higher levels than those of whole glomeruli when DL-glyceraldehyde or D-fructose was used as substrate. When cells were incubated in medium containing 55 mM glucose or galactose, a large amount of sorbitol or galactitol was accumulated intracellularly. The accumulation of polyols was effectively blocked by an aldose reductase inhibitor, ICI 128436. These results suggest that the polyol pathway exists in mesangial cells of rat glomeruli and may play a role in the development of mesangial cell dysfunction found in STZ-D rats.     

Effect of aldose reductase inhibitor (sorbinil) on integration of polyol pathway, pentose phosphate pathway, and glycolytic route in diabetic rat lens

This study examines the effect of an aldose reductase inhibitor (sorbinil) on the flux of specifically labeled glucose through alternative pathways of metabolism in the lens of normal and diabetic rats 1 wk after the induction of diabetes with alloxan. In the diabetic rat lens, there was an apparent increase in the flux of glucose through the pentose phosphate pathway (PPP), as measured by the difference in the yields of 14CO2 from [1-14C]glucose and [6-14C]glucose [C1-C6], this value was 0.087 +/- 0.005 and 0.263 +/- 0.034 mumol X g lens-1 X h (mean + SE of 6 values) for control and diabetic rats, respectively; sorbinil treatment decreased the values to 0.065 +/- 0.008 and 0.171 +/- 0.028, respectively. With glucose tritiated on carbon 2 or 3, it has been shown that the flux of glucose through the polyol route is increased, whereas the flux through the glycolytic pathway is decreased in the diabetic rat lens; both are restored toward normal in the sorbinil-treated diabetic group. These results suggest that the dual effects of diabetes in increasing the lens content of glucose and glucose 6-phosphate and the flux of glucose in the polyol pathway will result in an increased utilization of NADPH and production of NADH, factors favoring the flow of glucose through the PPP and restricting the glycolytic route in the diabetic rat lens. The inhibition of aldose reductase by sorbinil tends to normalize the redox state of the nicotinamide nucleotides, reimposing the NADPH limitation on the PPP and increasing the availability of NAD+ for the glycolytic route.     

Diabetic retinopathy may predict the renal outcomes of patients with diabetic nephropathy

Background: The patients with Type 2 diabetes mellitus (T2DM) and diabetic retinopathy (DR) are prone to develop diabetic nephropathy (DN). In this study, we aimed to clarify the relationship between DR and the progression of DN in patients with T2DM.

Methods: In the cross-section study, 250 patients with T2DM and biopsy-proven DN were divided into two groups: 130 in the DN without DR group (DN group) and 120 in the DN?+?DR group. Logistic regression analysis was performed to identify risk factors for DR. Of the above 250 patients, 141 were recruited in the cohort study who received follow-up for at least 1 year and the influence of DR on renal outcome was assessed using Cox regression. Renal outcome was defined as the progression to end-stage renal disease (ESRD).

Results: In the cross-section study, the severity of glomerular lesions (class IIb?+?III) and DM history?>10 years were significantly associated with the odds of DR when adjusting for baseline proteinuria, hematuria, e-GFR, and interstitial inflammation. In the cohort study, a multivariate COX analysis demonstrated that the DR remained an independent risk factor for progression to ESRD when adjusting for important clinical variables and pathological findings (p?Conclusions: These findings indicated that the severity of glomerular lesions was significantly associated with DR and DR was an independent risk factor for the renal outcomes in patients with DN, which suggested that DR may predict the renal prognosis of patients with T2DM and DN.     

Protein kinase C-delta mediates neuronal apoptosis in the retinas of diabetic rats via the Akt signaling pathway

OBJECTIVE—Protein kinase C (PKC)-δ, an upstream regulator of the Akt survival pathway, contributes to cellular dysfunction in the pathogenesis of diabetes. Herein, we examined the role of PKC-δ in neuronal apoptosis through Akt in the retinas of diabetic rats.RESEARCH DESIGN AND METHODS—We used retinas from 24- and 35-week-old male Otsuka Long-Evans Tokushima fatty (OLETF) diabetic and Long-Evans Tokushima Otsuka (LETO) nondiabetic rats. To assess whether PKC-δ affects Akt signaling and cell death in OLETF rat retinas, we examined 1) PKC-δ activity and apoptosis; 2) protein levels of phosphatidylinositol 3-kinase (PI 3-kinase) p85, heat shock protein 90 (HSP90), and protein phosphatase 2A (PP2A); 3) Akt phosphorylation; and 4) Akt binding to HSP90 or PP2A in LETO and OLETF retinas in the presence or absence of rottlerin, a highly specific PKC-δ inhibitor, or small interfering RNAs (siRNAs) for PKC-δ and HSP90.RESULTS—In OLETF retinas from 35-week-old rats, ganglion cell death, PKC-δ and PP2A activity, and Akt-PP2A binding were significantly increased and Akt phosphorylation and Akt-HSP90 binding were decreased compared with retinas from 24-week-old OLETF and LETO rats. Rottlerin and PKC-δ siRNA abrogated these effects in OLETF retinas from 35-week-old rats. HSP90 siRNA significantly increased ganglion cell death and Akt-PP2A complexes and markedly decreased HSP90-Akt binding and Akt phosphorylation in LETO retinas from 35-week-old rats compared with those from nontreated LETO rats.CONCLUSIONS—PKC-δ activation contributes to neuro-retinal apoptosis in diabetic rats by inhibiting Akt-mediated signaling pathways.Protein kinase C (PKC)-δ, a ubiquitously expressed isoform of the novel PKC subfamily, mediates an anti-apoptotic signaling cascade through the phosphatidylinositol 3-kinase (PI 3-kinase)–mediated survival pathway (1,2) and also promotes apoptosis by interfering with Akt signaling (3–5).Akt is a downstream target of PI 3-kinase that plays an integral role in cell survival. Dysregulation of Akt is frequently observed in diseases such as cancers and diabetes (6–8). PI 3-kinase activates Akt through the phosphorylation of two key regulatory residues, Thr308 and Ser473, on Akt. Phosphorylation of both residues is necessary for full activation of Akt and subsequent regulation of many PI 3-kinase–mediated biological responses (9,10).Protein phosphatase 2A (PP2A), a major cellular serine/threonine phosphatase, regulates the phosphorylation state of cellular proteins in various pathological conditions (11–13). Recently, it has been reported that PP2A is involved in the regulation of cell proliferation and survival through its ability to dephosphorylate Akt (11–15). Furthermore, heat shock protein 90 (HSP90) counteracts the effect of PP2A in cells through direct binding to Akt, protecting Akt from PP2A-mediated dephosphorylation and thus functioning as a positive regulator of Akt signaling (13,15,16). Of note, numerous reports have suggested that Akt- or HSP-mediated cytoprotection is regulated by PKC (1,5,13,17,18).Otsuka Long-Evans Tokushima fatty (OLETF) rats are a genetic animal model of late onset of hyperglycemia. Animals spontaneously develop type 2 diabetes and exhibit hyperglycemia and insulin resistance at 20–40 weeks of age (19–21). Recently, we reported that PKC-δ activation is involved in neuronal apoptosis in 35-week OLETF rat retinas (22); however, a direct association between PKC-δ and Akt was not defined.Therefore, we examined effects of PKC-δ on Akt-mediated survival pathways and neuronal apoptosis in the retinas of diabetic OLETF rats.     

Caspase activation in retinas of diabetic and galactosemic mice and diabetic patients

Apoptosis of retinal capillary cells begins early in diabetes and likely contributes to the capillary obliteration that is an important feature of diabetic retinopathy. Caspases are proteolytic enzymes that are closely involved in the induction and execution phases of apoptosis, but their role in the development of diabetic retinopathy has not been studied previously. Our study focused on the measurement of activities of multiple caspases in retinas of mice at different durations of diabetes. Several caspases (including caspases-1, -2, -6, -8, and -9) were activated as early as 2 months of diabetes. The caspases activity pattern changed with increasing duration of disease, suggesting a slowly developing caspases cascade. Activities of executioner caspases (e.g., cas-6 and -3) became elevated after longer duration of diabetes, and the induction of cas-3 activity was associated with the duration of diabetes at which capillary cells begin to show evidence of undergoing apoptosis. Retinas from patients with type 2 diabetes likewise showed a significant increase in activities of cas-1, -3, -4, and -6. For comparison, retinal caspases were also measured in experimental galactosemia, another model that develops a diabetic-like retinopathy. The pattern of caspases activation differed between diabetes and galactosemia, but cas-1 activity became elevated soon after elevation of blood hexose concentration in both. Caspases offer new therapeutic targets to test the role of apoptosis in the development of diabetic retinopathy.     

Ascorbic acid metabolism and polyol pathway in diabetes

It has been reported previously that the plasma concentration of ascorbic acid (AA) is reduced in streptozocin-induced diabetic rats and can be normalized by treatment with the aldose reductase inhibitor tolrestat. This study was designed to investigate further the relationship between the polyol pathway and AA metabolism in diabetic rats. Disturbance of AA metabolism was demonstrable after 1 wk of diabetes. Dietary myo-inositol supplementation was effective in normalizing plasma AA levels, as was treatment with tolrestat. In untreated diabetes, despite low plasma AA concentration, there was increased urinary excretion of AA that was reversed by treatment with either tolrestat or myo-inositol. In contrast, AA supplementation normalized plasma AA concentrations while further increasing urinary AA excretion. The abnormality of AA metabolism was less severe in galactose-fed rats, which had normal plasma AA levels and only minor increases in urinary AA excretion. These studies demonstrated a disturbance in the regulation of plasma and urinary AA concentration in experimental diabetes and confirmed the relationship of AA with the polyol pathway. Because AA has many important biological functions, abnormalities of AA metabolism could be important in the pathogenesis of some diabetic complications. The interaction of the polyol and AA pathways suggests that this could be another site of action for aldose reductase inhibitors.     

Enzymatic vitrectomy for diabetic retinopathy and diabetic macular edema

The aim of this paper is to determine the role of enzymatic vitrectomy performed by intravitreal injection of autologous plasmin enzyme (APE) in the management of diabetic retinopathy and diabetic macular edema (DME). Diabetic patients with proliferative diabetic retinopathy or DME and evident posterior hyaloid adherence to the retinal surface were included. All cases were treated with an initial intravitreal injection of APE and reevaluated one month later, measuring changes in best-corrected visual acuity (BCVA), macular thickness and the status of the posterior hyaloid. A second APE injection was performed in cases with no evident posterior vitreous detachment (PVD) after the initial treatment. Sixty-three eyes were included in the present review. A complete PVD appeared in 38% of cases (24 eyes) after one injection of plasmin and the total increased to 51% (32 eyes) after the second injection, separated at least by one month. The central macular thickness improved in all cases (100%) and BCVA in 89%. Finally, in 50% of eyes with proliferative diabetic retinopathy, a high reduction of new vessels regression was observed. Enzymatic vitrectomy could be considered a good therapeutic alternative in diabetic retinopathy and macular edema.     

Potential contributory role of H-Ras, a small G-protein, in the development of retinopathy in diabetic rats

Hyperglycemia is thought to be the underlying factor in the development of diabetic retinopathy, but the mechanisms involved remain partially understood. Diabetes increases oxidative stress, and reactive oxygen species affect the interactions between a small-molecular- weight G-protein, H-Ras, and several of its effector proteins. The purpose of this study was to examine the regulatory role of H-Ras in glucose-induced apoptosis of retinal endothelial cells. The expressions of H-Ras and its effector protein (Raf-1) were compared in the retina obtained from diabetic rats (2-8 months' duration) and age-matched normal rats and in retinal endothelial cells exposed to high-glucose medium. The effect of inhibition of H-Ras function on glucose-induced capillary cell death and the potential involvement of oxidative stress in diabetes-induced activation of H-Ras were also determined. The expressions of H-Ras and Raf-1 were increased in the retina in diabetes, and antioxidant therapy prevented diabetes-induced increased protein and mRNA expressions. The inhibitors of Ras farnesylation inhibited glucose-induced nitric oxides and apoptosis in isolated retinal endothelial cells. Thus, the results suggest that functional activation of H-Ras might be one of the signaling steps involved in glucose-induced capillary cell apoptosis and supports the role of H-Ras in the development of retinopathy in diabetes.     

Direct measurement of polyol pathway activity in the ocular lens

A method to measure the polyol pathway metabolic flux in the intact rabbit lens by 13C nuclear magnetic resonance spectroscopy is described. In the lens exposed to 35.5 mM glucose, the polyol pathway accounts for 1/3 of the total glucose turnover. The high metabolic activity of the pathway suggests a significant alteration in the reduced to oxidized pyridine nucleotide ratio in the lens exposed to high glucose.     

Pericytes and the pathogenesis of diabetic retinopathy

Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B(+/-) mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B(+/-) mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B(+/-) mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B(+/-) mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B(+/-) mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.     

Increased phagocyte-like NADPH oxidase and ROS generation in type 2 diabetic ZDF rat and human islets: role of Rac1-JNK1/2 signaling pathway in mitochondrial dysregulation in the diabetic islet

OBJECTIVE

To determine the subunit expression and functional activation of phagocyte-like NADPH oxidase (Nox), reactive oxygen species (ROS) generation and caspase-3 activation in the Zucker diabetic fatty (ZDF) rat and diabetic human islets.

RESEARCH DESIGN AND METHODS

Expression of core components of Nox was quantitated by Western blotting and densitometry. ROS levels were quantitated by the 2′,7′-dichlorofluorescein diacetate method. Rac1 activation was quantitated using the gold-labeled immunosorbent assay kit.

RESULTS

Levels of phosphorylated p47^phox, active Rac1, Nox activity, ROS generation, Jun NH₂-terminal kinase (JNK) 1/2 phosphorylation, and caspase-3 activity were significantly higher in the ZDF islets than the lean control rat islets. Chronic exposure of INS 832/13 cells to glucolipotoxic conditions resulted in increased JNK1/2 phosphorylation and caspase-3 activity; such effects were largely reversed by SP600125, a selective inhibitor of JNK. Incubation of normal human islets with high glucose also increased the activation of Rac1 and Nox. Lastly, in a manner akin to the ZDF diabetic rat islets, Rac1 expression, JNK1/2, and caspase-3 activation were also significantly increased in diabetic human islets.

CONCLUSIONS

We provide the first in vitro and in vivo evidence in support of an accelerated Rac1–Nox–ROS–JNK1/2 signaling pathway in the islet β-cell leading to the onset of mitochondrial dysregulation in diabetes.Glucose-stimulated insulin secretion (GSIS) involves a series of metabolic and cationic events leading to translocation of insulin granules toward the plasma membrane for fusion and release of insulin into circulation (1–3). Insulin granule transport and fusion involve interplay between vesicle-associated membrane proteins on the insulin granules and docking proteins on the plasma membrane. In addition, a significant cross talk among multiple small G-proteins, including Arf6, Cdc42, and Rac1, was shown to be critical for GSIS (4–6). Several effector proteins for these G-proteins have been identified in the islet β-cell (4,7,8). We recently reported regulatory roles for Rac1 in the activation of phagocyte-like NADPH oxidase (Nox) and generation of reactive oxygen species (ROS) leading to GSIS (9).Excessive ROS generation is considered central to the development of diabetes complications. The generation of free radicals is relatively low under physiologic conditions; however, increased levels of circulating glucose promote intracellular accumulation of superoxides, leading to cellular dysfunction. Although mitochondria remain the primary source for free radicals, emerging evidence implicates Nox as a major source of extra-mitochondrial ROS. Nox is a highly regulated membrane-associated protein complex that promotes a one-electron reduction of oxygen to superoxide anion involving oxidation of cytosolic NADPH. The Nox holoenzyme consists of membrane and cytosolic components (Fig. 1). The membrane-associated catalytic core consists of gp91^phox and p22^phox, and the cytosolic regulatory core includes p47^phox, p67^phox, p40^phox, and Rac1. After stimulation, the cytosolic core translocates to the membrane for association with the catalytic core for functional activation of Nox. Immunologic localization and functional regulation of Nox have been described in clonal β-cells and in rat and human islets (10–13).Open in a separate windowFIG. 1.Schematic representation of Nox activation. Nox holoenzyme consists of cytosolic and membrane-associated components. Upon activation, Rac1, guanosine-5′-diphosphate (GDP) is converted to Rac1 guanosine-5′-triphosphate (GTP), which binds to p67^phox, and the complex translocates to the membrane. Existing evidence in other cell types suggests that phosphorylation of p47^phox also triggers its translocation to the membrane to form the Nox holoenzyme complex that culminates in the enzyme activation and associated increase in ROS.Recent findings from studies of pharmacologic and molecular biologic approaches suggest that ROS derived from Nox play regulatory “second-messenger” roles in GSIS (9–11,13,14). In addition to the positive modulatory roles for ROS in islet function, recent evidence also implicates negative modulatory roles for ROS in the induction of oxidative stress and metabolic dysregulation of the islet β-cell under the duress of glucolipotoxicity, cytokines, and ceramide (15). The generation of ROS in these experimental conditions is largely due to the activation of Nox, because inhibition of Rac1 or Nox activation markedly attenuated deleterious effects of these stimuli (15–17). Despite this compelling evidence, potential roles of Nox in islet dysfunction in animal models of type 2 diabetes remain unexplored. We therefore undertook the current study to examine the functional status of Nox in islets from the ZDF rat, which develops obesity, hyperinsulinemia, hyperglycemia, and a decline in β-cell function. We present evidence to suggest significant activation of Nox, ROS generation, and caspase-3 activation in the ZDF islets. Our findings also suggest similar metabolic defects in islets from type 2 diabetic human islets.     

Classification of diabetic retinopathy and diabetic macular edema

The global incidence and prevalence of diabetes mellitus (DM) have reached epidemic proportions. Estimates indicate that more than 360 million people will be affected by DM by 2030. All of these individuals will be at risk of developing diabetic retinopathy (DR). It is extremely important to categorize, classify and stage the severity of DR in order to establish adequate therapy. With proper management more than 90% of cases of visual loss can be prevented. The purpose of the current paper is to review the classification of DR with a special emphasis on the International Clinical Disease Severity Scale for DR. This new classification is simple to use, easy to remember and based on scientific evidence. It does not require specialized examinations such as optical coherence tomography or fluorescein angiography. It is based on clinical examination and applying the Early Treatment of Diabetic Retinopathy Study 4:2:1 rule.     

糖尿病视网膜病变激光光凝术的疗效观察

目的观察糖尿病性视网膜病变(diabetic retinopathy,DR)激光光凝疗效,探讨DR激光光凝术的治疗时机和治疗方式。方法对79例(114眼)DR患者,根据分期、病情,选择不同方式的光凝治疗,记录患者激光前及激光后1⁶个月的最佳视力及眼底血管荧光造影(FFA)情况,评定疗效。结果 79例(114眼)DR患者接受光凝治疗前后视力及FFA结果表明,非增生性DR(nonproliferative diabetic retinopathy,NPDR)患者激光光凝疗效优于增生期DR(proliferative diabetic retinopathy,PDR)患者。结论眼底激光是治疗DR有效、安全的方法。严格规范的治疗方式,合理的治疗时机,可保存中心视力,提高疗效,有效治疗糖尿病视网膜病变。     

Vasodilation and the etiology of diabetic retinopathy: a new model

The evidence in support of the theory that retinal vascular stretching leads to leakage, formation of microaneurysms, and neovascularization is reviewed. The efficacy of photocoagulation and vitrectomy in controlling retinal microangiopathy accompanying diabetes is shown to depend upon reduction of the vascular dilatation. It is possible that the vascular dilatation in diabetes results from high blood glucose levels increasing oxygen consumption in the inner retina, with a resulting vascular dilatation to supply increased oxygen to the retina. This retinal vascular dilatation is the initial cause of the vascular pathology in diabetes.     

Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.