Development Of Late Diabetic Complications Research Articles

Hypercholesterolemia antagonized heart adaptation and functional remodeling of the mitochondria observed in acute diabetes mellitus subjected to ischemia/reperfusion injury.

Intrinsic cardioprotective mechanisms become activated in the early diabetes mellitus (DM) and this may protect the heart from ischemia/reperfusion (I/R) similarly as in case of ischemic preconditioning. However, this protection may by blunted in the presence of cardiovascular risk factors. Assuming that hypercholesterolemia (HCH) frequently accompanies DM, this study extends findings from separate models of DM and HCH by investigation the impact of HCH on DM-induced changes, including those of compensatory nature, in rat heart and its mitochondria. We used a factorial design with all combinations of treatment factors DM and HCH: control rats (C) and streptozotocin-treated rats (DM), both on standard chow (C and DM) and fed fat-cholesterol diet (HCH and DM-HCH). Isolated, Langendorff perfused hearts were subjected to 30 min global ischemia followed by reperfusion. Significantly increased levels of cholesterol in DM-HCH after I/R injury abrogated compensatory fluidization characteristic of DM mitochondria membranes. Concomitantly, the mitochondrial Mg2+-ATPase activity in DM-HCH was depressed. In comparison with DM, which showed significantly reduced size of myocardial infarction with simultaneously improved recovery of contractile function due to conditioning, DM-HCH hearts exhibited attenuated resistance to I/R injury. Taken together, cholesterol-enriched diet was associated with inflicting damage and has been implicated in the mechanisms leading to suppression of cardiac protection presented in diabetic group. Apparently, DM and HCH are factors which are not additive in their effects, therefore, caution should be exercised, when interpreting findings from studies considering these factors in isolation. Our findings suggest that this complex condition could accelerate the development of late diabetic complications.

Methylglyoxal and Advanced Glycation End Products in Patients with Diabetes - What We Know so Far and the Missing Links.

Hyperglycemia explains the development of late diabetic complications in patients with diabetes type 1 and type 2 only partially. Most therapeutic efforts relying on intensive glucose control failed to decrease the absolute risk for complications by more than 10%, especially in patients with diabetes type 2. Therefore, alternative pathophysiological pathways have to be examined, in order to develop more individualized treatment options for patients with diabetes in the future. One such pathway might be the metabolism of dicarbonyls, among them methylglyoxal and the accumulation of advanced glycation end products. Here we review currently available epidemiological data on dicarbonyls and AGEs in association with human diabetes type 1 and type 2.

SERUM PROLACTIN LEVELS IN TYPE-II DIABETES MELLITUS WITH RETINOPATHY PATIENTS IN AND AROUND HYDERABAD

Background & Objectives: Diabetes is a disease of metabolic dysregulation. Hyperglycemia and oxidative stress play a role in the development of late diabetic complications. Increased retinal vasopermeability occurs early in diabetes and is crucial for the development of sight-threatening diabetic retinopathy. Serum prolactin is proteolytically processed to vasoinhibins that inhibit the excessive retinal vasopermeability related to diabetic retinopathy. The aim is to study the role of serum prolactin and lipid profile in the pathogenesis of retinopathy in type 2 diabetics and to correlate the changes in serum prolactin levels. Methods: A case control study was done with 90 patients divided into 3 groups (healthy controls, Type 2 Diabetes without retinopathy and Type 2 Diabetes with retinopathy) with inclusion and exclusion criteria. Fasting blood samples were collected and fasting plasma glucose, serum Prolactin were measured. Multiple comparisons between different groups were done using ANOVA test. Results: In the present study decreased serum prolactin levels were observed in patients of Type 2 Diabetes with retinopathy compared to Type 2 Diabetes without retinopathy and controls. Mean ± S.D of Fasting plasma glucose, was highest in Group 3. Mean ± S.D of serum prolactin (7.737 ± 2.63) was low in Group 3. Interpretations & Conclusion: The circulating levels of prolactin were decreased in patients with diabetic retinopathy due to glycosylation and were higher in diabetic patients without retinopathy and healthy controls. Increased prolactin levels influence the progression of retinopathy after its intraocular conversion to vasoinhibins which can reduce the pathological retinal vasopermeability in diabetes and increase in prolactin can be considered to have protective role in pathogenesis of diabetic retinopathy and also may be considered as a treatment option for retinopathy. Key words: Prolactin; Diabetic retinopathy; Vasoinhibins; Retinal vasopermeability.

Status of serum magnesium in Egyptian children with type 1 diabetes and its correlation to glycemic control and lipid profile.

Diabetes mellitus has been suggested to be the most common metabolic disorder associated with magnesium deficiency, having 25% to 39% prevalence. This deficit could be associated with the development of late diabetic complications, especially macroangiopathy.We aimed to evaluate the status of serum Mg in children with type 1 diabetes and assess its relation to glycemic control and lipid profile.We included 71 Egyptian children with type 1diabetes having their follow-up at Pediatric Endocrinology outpatient clinic, Zagazig University Hospital and 71 age- and sex-matched control. We measured Serum magnesium, HbA1c, and lipid profile in all study subjects.Diabetic children had significantly lower serum magnesium level compared to control children (1.83 ± .27 mg/dL in diabetic children versus 2.00 ± .16 mg/dL in control children). Taking cut-off level of serum magnesium <1.7 mg/dL for definition of hypomagnesemia, hypomagnesemia was detected in 28.2% of diabetic children compared to 9.9% of control children. In diabetic patients, there was statistically significant difference in HbA1c between hypomagnesemic and normomagnesemic group being higher in the low magnesium group, as it is mean ± SD was 11.93 ± 3.17 mg/dL in group I versus 8.92 ± 0.93 mg/dL in the normomagnesemic group. Serum magnesium was found to be positively correlated with HDL (P < 0.001), and negatively correlated with age, HbA1c, triglycerides, total cholesterol, LDL, and duration of diabetes (P < 0.001).We concluded that total serum magnesium was frequently low in Egyptian children with type 1 diabetes and it is correlated with HbA1c and with lipid profile. Hypomagnesemia was more evident in patients with poor diabetic control and those with higher atherogenic lipid parameters. We suggest that low serum magnesium may be included in pathogenesis of poor glycemic control and abnormal lipid profile in children with type 1 diabetes. We need to perform further studies on giving magnesium supplements in diabetic children with hypomagnesemia to observe the effect of correction of serum magnesium on glycemic control, lipid profile, and the risk of diabetic complications.

Superoxide Dismutase and Glutathione Peroxidase Levels in Patients with Long Standing Type 2 Diabetes in Port Harcourt, Rivers State, Nigeria

Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. It is associated with increased oxidative stress. This study evaluates the levels of the antioxidant enzymes superoxide dismutase (SOD) and gluthathione peroxidase (GPx), as a measure of antioxidant status in Type 2 diabetics. A total of 182 subjects were involved in the study, of which 109 were diabetics (Test) and 73 non-diabetics (Controls). The criterion for the classification as a diabetic was based on subjects having glycated haemoglobin (HbA1c) levels ≥ 6.5%. A structured interviewer administered questionnaire was used as an aid in the collection of demographic and lifestyle data from the subjects. HbA1c was estimated quantitatively by immunochemical method. SOD and GPx was measured by the sandwich-enzyme linked immunosorbent assay (ELISA) method. Glucose oxidase method was used for the determination of fasting plasma glucose (FPG). Mean SOD and GPx values in the diabetic subjects were significantly lower (p 0.05) in the levels of SOD and GPx in diabetic subjects with respect to age differences, even though the enzyme levels decreased with increasing age. FPG and HbA1c levels were significantly higher (p<0.05) in the diabetics as compared to the controls. Type 2 diabetes is associated with decreased antioxidative status as the levels of the antioxidant enzymes SOD and GPx were significantly reduced in the diabetic subjects. The increasing duration of the illness further depresses the antioxidative system. As the disease condition progresses, antioxidative parameters are further depleted, showing an increase in oxidative stress. It is thus recommended that antioxidative therapy be incorporated in the management/therapy of Type 2 diabetics, to supplement the endogenous anti-oxidative system, as this could prevent or delay progression of the disease and the development of late diabetic complications.

The Fluorescence Identification of Advanced Glycation End Products in Streptozotocin−Induced Diabetic Rats’ Plasma Samples

The plasma samples obtained from non-diabetic and diabetic rats were examined by fluorescence spectroscopy in order to find specific spectroscopic biomarkers for the monitoring and development of late diabetic complications. We studied 10 non-diabetic rats (8 middle-aged rats and 2 younger). After the spectrofluorimetrically determination (370 nm/432 nm) of AGEs in healthy rats, diabetes was induced by the intravenous injection of streptozotocin. AGEs were determined again at 1 week interval by using the same method. The results show that emission bands appearing at 405, 420 and 432 in all examined samples obtained from healthy rats were increased in intensity in all tested diabetic rats. The emission intensities were relatively the same in healthy rats’ plasma samples. Therefore, the high of the emission maximum at around 405 nm was between 727 - 1653 nm, the height of the peak around 420 nm was between 807 and 1574 nm, while the maximum of the peak around 432 nm was between 748 nm and 1475 nm. Upon diabetes induction, the high of the emission band at around 432, which is assigned to AGEs, increased about 2-fold. The fluorescence emission spectra of plasma samples are able to discriminate the diabetic rats from the healthy controls.

Organ-specific affects of diabetes on mitochondrial function

Increased production of reactive oxygen species (ROS), especially by the mitochondria, is considered to be a central mechanism underlying the development of late diabetic complications. This study aims to determine how mitochondrial functions are changed in different organs during diabetes in order to determine if mitochondrial ROS production effects the development of diabetic complications.

The advanced glycation end product methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in childhood diabetes.

Advanced protein glycation is an important mechanism for the development of late diabetic complications including atherosclerosis. Methylglyoxal-derived hydroimidazolone-1 is the most abundant advanced glycation end product in human plasma. To investigate the relationship between methylglyoxal-derived hydroimidazolone-1 and early signs of atherosclerosis in children and adolescents with type 1 diabetes and healthy controls. A total of 314 diabetes patients aged 8-18 years were compared with 120 healthy controls. Serum methylglyoxal-derived hydroimidazolone-1 was measured by immunoassay. Atherosclerosis was evaluated by assessing carotid intima-media thickness by ultrasound, arterial stiffness by Young's modulus and inflammation by C-reactive protein. Methylglyoxal-derived hydroimidazolone-1 was significantly increased in the diabetes group compared with controls, 155.3 (standard deviation (SD) = 41.0) versus 143.0 (SD = 35.1) U/mL, p = 0.003, as was C-reactive protein, median 0.51 (0.27, 1.83) versus 0.31 (0.19, 0.67) mg/L, p < 0.001. There was no significant difference between the groups regarding carotid intima-media thickness or Young's modulus. Multiple regression analysis showed a significant positive association between methylglyoxal-derived hydroimidazolone-1 and C-reactive protein in the diabetes group. Serum levels of methylglyoxal-derived hydroimidazolone-1 in diabetes patients are increased and associated with low-grade inflammation, but not yet arterial stiffness or wall thickness. This indicates that methylglyoxal-derived hydroimidazolone-1 may be important in the early phase of the accelerated atherosclerotic process in diabetes.

Epidemiological aspects of type 2 diabetes in the young

Aim. To study prevalence and incidence of type 2 diabetes in the young population of Tyumen region. Materials and methods. The study included 201 adult patient with type 2 diabetes mellitus (DM). The first group included 99 patients with disease onset before 35 years, while the second group included 102 patients with disease onset after 40 years. We have used a Tyumen regional diabetes register data, covering last 10 years period. We assessed the prevalence and incidence of type 2 DM and its vascular complications. Results. The prevalence of type 2 DM in patients with disease manifest before 35 years increased by 2,7 times and the incidence ? by 2,1 times during last 10 years. We noted predominance of retinopathy and nephroopthy in the structure of vascular complications in this group. Conclusion. Patients with type 2 DM onset before 35 years are characterized by increasing prevalence and incidence during last 10 years, as well as rapid development of late diabetic complications with a predominance of microangiopathy.

Evaluation of paraoxonase 1 arylesterase activity and lipid peroxide levels in patients with type 1 diabetes

Poor metabolic control of type 1 diabetes is one of the most important factors accelerating the development of late diabetic complications. Several other factors that might contribute to this process are currently being investigated. Low paraoxonase 1 (PON1) activity and high lipid peroxide (LPO) levels contribute to endothelial damage, but it remains unclear whether they are critical for the development of late diabetic complications. The aim of the study was to evaluate PON1 arylesterase activity and LPO levels in patients with type 1 diabetes and to investigate whether these parameters are associated with metabolic control and late complications. Moreover, we aimed to establish whether PON1 activity and LPO levels differ between women and men with type 1 diabetes. The study involved 80 patients with type 1 diabetes and 24 healthy subjects. PON1 activity was measured by a spectrophotometric method. LPO levels were measured by a commercial assay kit. Diabetic patients had lower PON1 activity and higher LPO levels than healthy people. We observed a negative correlation between PON1 activity and LPO levels in diabetic patients. There was no association between PON1 activity or LPO levels and metabolic parameters or late diabetic complications. There was a positive correlation between LPO levels and the body mass index (BMI) in women with type 1 diabetes. Our study showed that low PON1 activity and high LPO levels are not the most critical factors involved in late diabetic complications in type 1 diabetes. Increased LPO levels in women with type 1 diabetes may result from enhanced lipogenesis in this subgroup compared with diabetic men.

Protection of the vascular endothelium in experimental situations

One of the factors proposed as mediators of vascular dysfunction observed in diabetes is the increased generation of reactive oxygen species (ROS). This provides support for the use of antioxidants as early and appropriate pharmacological intervention in the development of late diabetic complications. In streptozotocin (STZ)-induced diabetes in rats we observed endothelial dysfuction manifested by reduced endothelium-dependent response to acetylcholine of the superior mesenteric artery (SMA) and aorta, as well as by increased endothelaemia. Changes in endothelium-dependent relaxation of SMA were induced by injury of the nitric oxide radical (·NO)-signalling pathway since the endothelium-derived hyperpolarising factor (EDHF)-component of relaxation was not impaired by diabetes. The endothelial dysfunction was accompanied by decreased ·NO bioavailabity as a consequence of reduced activity of eNOS rather than its reduced expression. The results obtained using the chemiluminiscence method (CL) argue for increased oxidative stress and increased ROS production. The enzyme NAD(P)H-oxidase problably participates in ROS production in the later phases of diabetes. Oxidative stress was also connected with decreased levels of reduced glutathione (GSH) in the early phase of diabetes. After 10 weeks of diabetes, adaptational mechanisms probably took place because GSH levels were not changed compared to controls. Antioxidant properties of SMe1EC2 found in vitro were partly confirmed in vivo. Administration of SMe1EC2 protected endothelial function. It significantly decreased endothelaemia of diabetic rats and improved endothelium-dependent relaxation of arteries, slightly decreased ROS-production and increased bioavailability of ·NO in the aorta. Further studies with higher doses of SMe1EC2 may clarify the mechanism of its endothelium-protective effect in vivo.

Flow cytometric analysis of glyoxalase‐1 expression in human leukocytes

Altered glyoxalase-1 (GLO-1) activity and expression is associated with the development of late diabetic complications, malignancy and oxidative stress- and aging-related diseases. In the present study, we developed a flow cytometry method for GLO-1 detection in human leukocytes isolated from peripheral blood samples to investigate GLO-1 expression in leukocyte subsets from type 1 and 2 diabetes mellitus patients (n = 11) and healthy subjects (n = 8). The flow cytometry analysis of GLO-1 in leukocytes showed that expression index of GLO-1-positive cells was slightly increased in mononuclear leukocytes from diabetic patients. This result correlated with the increase in GLO-1 activity in the whole blood samples of type 2 diabetes patients. In conclusion, the present study demonstrates that flow cytometry is suitable for the detection of the GLO-1 enzyme in human leukocytes and that this method could be used to investigate the fast adaptation of the glyoxalase system related to the pathogenesis of late complications of diabetes mellitus and other glycation stress-related disorders.

Knowledge after five-day teaching program in intensive insulin therapy performed at the onset of type 1 diabetes influence the development of late diabetic complications

We evaluated the influence of baseline diabetic knowledge on clinical course of type 1 diabetes treated with intensive functional insulin therapy (IFIT) from the onset of the disease. 86 subjects with newly diagnosed type 1 diabetes, aged 23.4 ± 5.1 attended a five-day structured training program in IFIT at baseline, followed by a test consisting of 20 questions. Patients were divided into subgroups according to test results: group A > 16, group B 12–16 and group C < 12 scores. At follow-up (7.1 ± 1.5 years) metabolic control and development of microangiopathy were assessed. Patients with low knowledge at baseline had higher HbA1c levels than subjects with higher knowledge (group C: 9.2 ± 1.9 vs. group A: 7.7 ± 1.5%, p < 0.05 and vs. group B: 7.8 ± 1.6%, p < 0.05), higher BMI (group C: 23.9 ± 3.2 vs. group A: 21.8 ± 3.1 kg/m 2, p < 0.05) and lower HDL-cholesterol level (group C: 1.8 ± 0.5 vs. group A: 2.0 ± 0.3 mmol/l, p < 0.05). Patients with retinopathy and albuminuria at follow-up had lower level of diabetic knowledge at baseline (respectively: 12.5 ± 3.6 vs. 14.2 ± 3.3 scores, p < 0.05; and 12.6 ± 2.9 vs. 14.1 ± 3.5 scores, p < 0.05). The development of microangiopathy was associated with lower diabetic knowledge (RR = 3.71; 95%CI: 1.15–12.01, p = 0.02 for retinopathy and RR = 4.33; 95%CI: 0.98–19.10, p = 0.04 for microalbuminuria). The higher diabetic knowledge at baseline the better metabolic control and lower risk of microangiopathy in the future.

RAGE-dependent glyoxalase-1 impairment mediates functional deficits in diabetic neuropathy

Introduction: Glycation of proteins, nucleotides and phospholipids contributes to the development of late diabetic complications at least in part via interaction with their cellular receptor RAGE. Reactive intermediates of AGE formation such as glyoxal, methylglyoxal (MG) and other dicarbonyl compounds are detoxified by the glyoxalase-system. Since RAGE-/– mice are partly protected from late diabetic complications including diabetic neuropathy (DN), we studied the expression of the AGE-detoxifying enzyme glyoxalase-1 (GO1) in peripheral nerves and dorsal root ganglia (DRG) of healthy and diabetic wildtype (WT)- and RAGE-/– mice to determine a possible interaction of RAGE and GO1.

RAGE modulates neuronal glyoxalase-1 transcription, expression and activity

Introduction: Methylglyoxal (MG) is a precursor of a variety of advanced glycation endproducts (AGEs), which are supposed to contribute to the development of late diabetic complications via interaction with their cellular receptor RAGE. MG and other AGE-precursors are detoxified by the glyoxalase-system.

Understanding RAGE, the receptor for advanced glycation end products

Advanced glycation end products (AGEs), S100/calgranulins, HMGB1-proteins, amyloid-beta peptides, and the family of beta-sheet fibrils have been shown to contribute to a number of chronic diseases such as diabetes, amyloidoses, inflammatory conditions, and tumors by promoting cellular dysfunction via binding to cellular surface receptors. The receptor for AGEs (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules acting as counter-receptor for these diverse molecules. Engagement of RAGE converts a brief pulse of cellular activation to sustained cellular dysfunction and tissue destruction. The involvement of RAGE in pathophysiologic processes has been demonstrated in murine models of chronic disease using either a receptor decoy such as soluble RAGE (sRAGE), RAGE neutralizing antibodies, or a dominant-negative form of the receptor. Studies with RAGE-/- mice confirmed that RAGE contributes, at least in part, to the development of late diabetic complications, such as neuropathy and nephropathy, macrovascular disease, and chronic inflammation. Furthermore, deletion of RAGE provided protection from the lethal effects of septic shock caused by cecal ligation and puncture (CLP). In contrast, deletion of RAGE had no effect on the host response in delayed-type hypersensitivity (DTH). Despite the lack of effect seen in adaptive immunity by the deletion of RAGE, administration of the receptor decoy, sRAGE, still afforded a protective effect in RAGE-/- mice. Thus, sRAGE is likely to sequester ligands, thereby preventing their interaction with other receptors in addition to RAGE. These data suggest that, just as RAGE is a multiligand receptor, its ligands are also likely to recognize several receptors in mediating their biologic effects.

Vascular repair and regulation in kidney disease: Overview

Vascular repair and regulation in kidney disease: Overview

Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kappaB.

Increased oxidative stress and subsequent activation of the transcription factor NF-kappaB has been linked to the development of late diabetic complications. To determine whether oxidative stress dependent NF-kappaB activation is evident in patients with diabetic nephropathy we used an Electrophoretic Mobility Shift Assay based semiquantitative detection system which enabled us to determine NF-kappaB activation in ex vivo isolated peripheral blood mononuclear cells. We examined 33 patients with diabetes mellitus (Type I and Type II). Patients with diabetic nephropathy showed higher NF-kappaB binding activity in Electrophoretic Mobility Shift Assays and stronger immunohistological staining for activated NF-kappaBp65 than patients without renal complications. NF-kappaB binding activity correlated with the degree of albuminuria (r = 0.316) and with thrombomodulin plasma concentrations (r = 0.33), indicative for albuminuria associated endothelial dysfunction. In a 3 day intervention study in which 600 mg of the antioxidant thioctic acid (alpha-lipoic acid) per day were given to nine patients with diabetic nephropathy oxidative stress in plasma samples was decreased by 48% and NF-kappaB binding activity in ex vivo isolated peripheral blood mononuclear cells by 38%. In conclusion, activation of the transcription factor NF-kappaB in ex vivo isolated peripheral blood mononuclear cells of patients with diabetes mellitus correlates with the degree of diabetic nephropathy. NF-kappaB activation is at least in part dependent on oxidative stress since thioctic acid (alpha-lipoic acid) reduced NF-kappaB binding activity.

The role of oxidative stress and NF-kappaB activation in late diabetic complications.

A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE's) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical-generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular function by binding to several binding sites including the receptor for AGE's, RAGE. Binding of AGE's (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox-sensitive transcription factor NF-kappaB in vitro and in vivo. Consistently, activation of NF-kappaB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant alpha-lipoic acid. The development of techniques allowing for a tissue culture independent measurement of NF-kappaB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation.

Beneficial Effect of Fetal Islet Grafting on Development of Late Diabetic Complications

Beneficial Effect of Fetal Islet Grafting on Development of Late Diabetic Complications