Secondary Complications Of Diabetes Mellitus Research Articles

SGLT2 inhibitor improves kidney function and morphology by regulating renal metabolism in mice with diabetic kidney disease

BackgroundDiabetic kidney disease (DKD) is a secondary complication of diabetes mellitus and a leading cause of chronic kidney disease. AimTo investigate the impact of long-term canagliflozin treatment on DKD and elucidate its underlying mechanism. MethodsDKD model was established using high-fat diet and streptozotocin in male C57BL/6J mice (n = 30). Mice were divided into five groups and treated for 12 weeks. 1) normal control mice, 2) DKD model, 3) mice treated low-dose of canagliflozin, 4) high-dose of canagliflozin and 5) β-hydroxybutyrate. Mice kidney morphology and function were evaluated, and a metabolomics analysis was performed. ResultsCanagliflozin treatment reduced blood creatinine and urine nitrogen levels and improved systemic insulin sensitivity and glucose tolerance in diabetic mice. Additionally, a decrease in histological lesions including collagen and lipid deposition in the kidneys was observed. β-hydroxybutyrate treatment did not yield a comparable outcome. The metabolomics analysis revealed that canagliflozin induced alterations in amino acid metabolism profiles in the renal tissue of diabetic mice. ConclusionCanagliflozin protects the kidneys of diabetic mice by increasing the levels of essential amino acids, promoting mitochondrial homeostasis, mitigating oxidative stress, and stimulating the amino acid-dependent tricarboxylic acid cycle.

Effect of vinpocetine alone and in combination with enalapril in experimental model of diabetic cardiomyopathy in rats: possible involvement of PDE-1/TGF-β/ Smad 2/3 signalling pathways.

Diabetic cardiomyopathy (DC) is one of the severe secondary complications of diabetes mellitus in humans. Vinpocetine is an alkaloid having pleiotropic pharmacological effects. The present study is designed to investigate the effect of vinpocetine in DC in rats. Rats were fed a high-fat diet for nine weeks along with single dose of streptozotocin after the second week to induce DC. The haemodynamic evaluation was performed to assess the functional status of rats using the Biopac system. Cardiac echocardiography, biochemical, oxidative stress parameters and inflammatory cytokine level were analysed in addition to haematoxylin-eosin and Masson's trichome staining to study histological changes, cardiomyocyte diameter and fibrosis, respectively. Phosphodiesterase-1 (PDE-1), transforming growth factor-β (TGF-β) and p-Smad 2/3 expression in cardiac tissues were quantified using western blot/RT-PCR. Vinpocetine treatment and its combination with enalapril decreased the glucose levels compared to diabetic rats. Vinpocetine improved the echocardiographic parameters and cardiac functional status of rats. Vinpocetine decreased the cardiac biochemical parameters, oxidative stress, inflammatory cytokine levels, cardiomyocyte diameter and fibrosis in rats. Interestingly, expressions of PDE-1, TGF-β and p-Smad 2/3 were ameliorated by vinpocetine alone and in combination with enalapril. Vinpocetine is a well-known inhibitor of PDE-1 and the protective effect of vinpocetine in DC is exerted by inhibition of PDE-1 and subsequent inhibition of the expression of TGF-β/Smad 2/3.

Treatment of Diabetic Foot Syndrome By Means of Hyaluronidase Infusion Therapy – Single Patient Case Report

Background: Diabetic foot syndrome (DFS) is one of the most severe secondary complications of diabetes mellitus. It is currently treated with improvement and maintenance of good glycemic control, pain drugs, antibiotics, and drugs and surgical measures to improve the vascular blood flow into the legs. In late stages, foot amputation (in part or total) is the only means to safe the patient’s life. Case Report: A 56-year-old woman with type 1 diabetes for more than 40 years, suffered from diabetic foot syndrome with complete closure of the arteria fibularis and a non-healing foot ulcer at the left leg. The need for lower ankle amputation was already determined. We tried to improve the vascular situation by means of a series of intravenous hyaluronidase infusions over a period of three weeks. An immediate improvement of the general condition was observed. The ulcer healed completely within 8 weeks, and a re-opening of the previously closed vessel as well as further additional collateral blood-flow into the left foot could be determined by means of an angiogram six months later. Discussion: The observed beneficial impact of intravenous hyaluronidase treatment on atherosclerotic lesions can be explained by the molecular action of the enzyme on the glycocalix, the extracellular hyaluronan layer that separates the endothelial cells from the blood stream. Successful treatment of DFS with hyaluronidase infusions has been reported already 50 years ago but research on this topic ceased, when stents and other apparently more compelling vascular treatment methods were detected. Conclusions: In a severe case of DFS, we were able to re-open a critical arterial vessel and improve the entire vascular blood flow by means of intravenous hyaluronidase infusions. Clinical studies are required to confirm the value of hyaluronidase infusions as treatment alternative to amputation for DFS.

Pancreas Transplantation Alone for Brittle Diabetes Mellitus

Only about 8% of all pancreas transplants for insulin-dependent diabetes mellitus are performed in the Pancreas Transplant Alone (PTA) category. PTAs are primarily performed in diabetic, non-uremic patients with unstable glucose control, hypoglycemia unawareness, and an increased risk of diabetes-related mortality, and who have failed all of the more traditional approaches to glycemic control. Tremendous, yet not widely noticed, progress in PTA outcome has been made over the past two decades. PTA is a very safe procedure with 1-and 5-year patient survival rates of 98.3% and 90.5% according to International Pancreas Transplant Registry (IPTR) data. Since the introduction of tacrolimus and mycophenolate mofetil maintenance therapy in the 1990s and the use of depleting antibody induction therapy, PTA graft survival rates at 1-and 5-years posttransplant are 87.2% and 65.0%. To avoid the need for a future kidney after pancreas (KAP) transplant due to impaired pretransplant native kidney function and the posttransplant use of calcineurin inhibitors, the estimated Glomerular Filtration Rate (eGFR) of PTA candidates should be well within the normal range and preferably > 80 mL/min/1.73m². PTAs with stable, long-term function have been shown to have a positive impact on secondary complications of diabetes mellitus. Considering the significantly improved outcome results, PTA should become the pancreas transplant option of choice before the manifestation of devastating secondary complications (kidney failure, cardio-cerebrovascular events, and blindness) that require simultaneous pancreas and kidney (SPK) transplants in qualified candidates, but with higher morbidity and mortality risks. It is important for diabetologists, endocrinologists, and other health professionals involved in the care of diabetic patients to learn about these positive PTA outcome results. Despite improvements in intensive insulin therapy, insulin-delivering devices, bioartificial pancreas, and islet transplantation, a successful PTA is the only treatment option for patients with brittle diabetes that consistently restores normal glucose homeostasis long-term without exposing recipients to the risks of severe hypoglycemia and prevents, halts, or reverses the development or progression of secondary diabetes complications.

Screening of Natural Molecules as Adjuvants to Topical Antibiotics to Treat Staphylococcus aureus from Diabetic Foot Ulcer Infections.

Diabetic foot ulcers (DFUs) are a common result of a complex secondary complication of diabetes mellitus. More than half of DFUs become infected due to frequent colonization with Staphylococcus aureus. The use of topical antibiotics is proposed, especially in combination with natural adjuvants, to minimize the negative impacts caused by generalized use of systemic antibiotics. In this study, 13 different phytochemicals—namely chalcone, juglone, cinnamic acid, trigonelline, Furvina—and four nitrovinylfuran derivatives—guaiazulene, α-bisabolol, farnesol and nerolidol—were selected to be tested as antibiotic enhancers. After minimum inhibitory and bactericidal concentration (MIC and MBC) determination of each molecule against different strains of S. aureus, including clinical isolates from diabetic foot wounds (CECT 976, Xu212, SA 1199B, RN4220, MJMC102, MJMC109, MJMC110 and MJMC111), their potentiation effects on the antibiotics fusidic acid, mupirocin, gentamicin, oxacillin and methicillin were evaluated through the disc diffusion method. Farnesol at sub-MIC was able to restore the activity of methicillin and oxacillin on the MJMC102 and MJMC111 strains, as well as two MRSA clinical isolates, and potentiated the effect of the remaining antibiotics. The results obtained demonstrate the great potential for the topical application of phytochemicals and derivatives as antibiotic resistance modifier agents to combat multidrug resistance in bacterial wound infections.

Pancreas transplantation would be easy if the recipients were not diabetic: A practical guide to post-operative management of diabetic complications in pancreas transplant recipients.

Diabetes mellitus remains a major public health problem throughout the United States with over $300billion spent in total cost of care annually. In addition to being a leading cost of kidney failure, diabetes causes a host of secondary hyperglycemic-related complications including gastroparesis and orthostatic hypotension. While pancreas transplantation has been established as an effective treatment for diabetes, providing long-term normoglycemia in recipients, the secondary complications of diabetes mellitus persist complicating the post-operative course of an otherwise successful pancreas transplantation. This review describes the mechanismand impact of diabetic gastroparesis and orthostatic hypotension in the post-operative course of pancreas transplant patients and analyzes the various treatment modalities, based on current data and extensive experience at our institution, to treat these respective complications. While gastroparesis and orthostatic hypotension remain challenging post-operative conditions, the establishment of institutional protocols and step-up treatment algorithms can help define more effective therapies.

Forensic interrogation of diabetic endothelitis in cardiovascular diseases and clinical translation in heart failure.

Diabetic heart disease (DHD) can be classified as a primary consequence from several pathophysiological manifestation of diabetes mellitus (DM) on cardiac tissues or secondarily in extracardiac tissues and is encountered as either primary or secondary complications of DM. Endothelitis is inflammation of the vascular endothelium and is likely to be seen in the majority of patients who start to manifest an end organ complication of DM in this case DHD. Diabetes is a leading cause for many cardiovascular syndromes and diseases including congestive heart failure (CHF) however much remains unknown about the transition from diagnosed DM to clinical state and the contribution of the various mechanical and counterregulatory systems in the manifested complaint. Diastolic heart failure or heart failure with preserved ejection fraction (DHF/HFpEF), accounts for half of all CHF presentations, has DM as a major contributor, however, there remain large gaps in clinical and pathophysiological understanding. This review aims to explore the microscopic aspects in diabetic endothelitis and provide a clinical link to with context to HFpEF.

Dietary and Lifestyle Modification in the Preventation of Secondary Complication of Diabetes Mellitus

Diabetes mellitus metabolic cum vascular syndrome of multiple aetiologies characterized by chronic hyperglycemia with disturbances of CHO, Fat and Protein metabolism resulting from defects in insulin secretion, insulin action or both. This disorder is frequently associated with long term disease, which can lead to failure of organs like eyes, kidneys, nerves, heart, and blood vessel. In recent years India has witnessed a rapidly exploding epidemic of Diabetes. Indeed, India today leads the world with its largest number of Diabetic people in any given country. WHO estimates there are 32 million with Diabetes in India with Diabetes in 2000, which is projected to rise by 80 million by the year 2030? Increase in prevalence is rapid in urban areas from 2% 1970s to 12% in 2000 and in rural areas also it is now beginning to increase. Nutrition is often said to be the cornerstone of diabetes care. The goal for nutritional management is optimal metabolic control through a balance between food intake, physical activity, and if necessary, medication to avoid complications.

Retinal and circulating miRNA expression patterns in diabetic retinopathy: An in silico and in vivo approach.

Diabetic retinopathy, a secondary complication of diabetes mellitus, can lead to irreversible vision loss. Currently, no treatment is approved for early phases of diabetic retinopathy. Modifications of the expression pattern of miRNAs could be involved in the early retinal damage of diabetic subjects. Therefore, we aimed at identification of dysregulated miRNAs-mRNA interactions that might be biomarkers and pharmacological targets for diagnosis and treatment of early diabetic retinopathy. A focused set of miRNAs was predicted through a bioinformatic analysis accessing to Gene Expression Omnibus dataset and enrichment of information approach (GENEMANIA-Cytoscape). Identification of miRNAs-mRNA interactions was carried out with miRNET analysis. Diabetes was induced in C57BL6J mice by streptozotocin and samples analysed at 5 and 10weeks after diabetes induction. Retinal ultrastructure of diabetic mice was analysed through electron microscopy. We used Real-time PCR, western blot analysis, elisa, and immunohistochemistry to study expression of miRNAs and possible targets of dysregulated miRNAs. We found that miR-20a-5p, miR-20a-3p, miR-20b, miR-106a-5p, miR-27a-5p, miR-27b-3p, miR-206-3p, and miR-381-3p were dysregulated in the retina and serum of diabetic mice. VEGF, brain-derived neurotrophic factor (BDNF), PPAR-α, and cAMP response element-binding protein 1 (CREB1) are targets of dysregulated miRNAs, which then modulated protein expression in diabetic retina. We found structural modifications in retinas from diabetic mice. Serum and retina of diabetic mice express eight dysregulated miRNAs, which modified the expression of VEGF, BDNF, PPAR-α, and CREB1, before vasculopathy in diabetic retinas.

Effect of diet with carbohydrate but without daily energy restriction on serum glucose, lactate, and selected mineral and lipid levels in streptozotocin-induced experimental diabetic rats

Objective: Type I diabetes is a disease characterised by an extreme reduction in serum insulin levels. Diet and exercise have gained considerable attention in the treatment of diabetes. Therefore, this study was carried out to investigate the effect of diet with carbohydrate but without daily energy restriction on various metabolites (glucose, triglycerides, cholesterol, lactate), some electrolytes (Ca, Mg, Na, K, P, Cl) and essential metals (Mn, Co, Cu, Se, Zn, Fe) in the blood of rats with streptozotocin-induced diabetes.Materials and methods: Thirty-three male rats were divided into four groups of standard rat diet (SR)-fed control, SR-diet fed diabetics, low carbohydrate-standard protein-high fat (LCSPHF) diet-fed diabetics, and very low carbohydrate-high protein-high fat (VLCHPHF) diet-fed diabetics. Diabetes was induced by an i.p. injection of 50 mg/kg streptozotocin. The rats were fed with the specially prepared diets for 28 days.Results: The decreased-serum Cl and the increased-serum glucose levels were only the difference between the controls and SR diet-fed diabetic rats regarding to measured parameters. Lowering carbohydrate and increasing fat ratio in diet caused an increase in serum cholesterol and triglyceride levels leading to an increased-serum Fe and Ca, and decreased-serum Na and Cu levels in diabetic rats.Conclusion: The serum mineral changes should be taken into consideration together with the changes in serum glucose, cholesterol, and triglyceride levels for the secondary complications of diabetes mellitus.

Aldose reductase inhibitory potential and anti-cataract activity of Punica granatum Linn. leaves against glucose-induced cataractogenesis in goat eye lens

Cataract is one of the primitive secondary complications of diabetes mellitus and contributes to 50% blindness worldwide. Aldose reductase (AR) is the first and rate limiting enzyme in the intracellular polyol pathway responsible for the development of cataract. Thus, there is an imperative need for modest, non-surgical way in order to treat cataract. In Ayurveda, Punica granatum (Pomegranate) is considered as “a pharmacy unto itself”. Pomegranate leaves are traditionally used for their anti-diabetic activity. In this study, we investigated AR inhibitory activity and anti-cataract potential of Pomegranate leaves in glucose - induced cataract in goat lens. AR inhibitory activity was evaluated in vitro in goat lenses. In glucose induced cataract model, goat lenses were incubated in artificial aqueous humor containing 55 mM glucose along with methanolic extract of Punica granatum leaves (MPGL) or quercetin for 72 h. After 72 h, photographic evaluation of the lens was carried out and the lens antioxidant parameters were determined. Different concentrations of MPGL were found to inhibit lens AR activity with an IC50 value of 83.55 ± 3.92 μg/ml. Quercetin was taken as positive control which exhibited 56.461% AR inhibition at a concentration of 500 μg/ml. Cataractous lenses exhibited marked opacity and decrease in the levels of reduced glutathione and superoxide dismutase. Treatment with MPGL and quercetin prevented the opacity and restored back the antioxidant activity. Together, Punica granatum leaves ameliorated glucose-induced cataractogenesis via AR inhibition, reduction in oxidative stress and improvement in antioxidant defense system.

Quercetin inhibited epithelial mesenchymal transition in diabetic rats, high-glucose-cultured lens, and SRA01/04 cells through transforming growth factor-β2/phosphoinositide 3-kinase/Akt pathway

Diabetic cataract (DC), an identified life-threatening secondary complication of diabetes mellitus, has proven to be a dilemma because of its multifactorial caused and progression. An increasing number of studies have shown that in addition to the maillard reaction, enhanced polyol pathway, and oxidative insults, epithelial mesenchymal transition (EMT) is related to the prevalence of DC. Quercetin, a classic flavonoid with multiple pharmacological effects has been reported to possess therapeutic efficacy in the management and treatment of this disease. However, the mechanism underlying its therapeutic efficacy in EMT of lens epithelial cells (SRA01/04) and contribution to resolving DC remains a mystery. Therefore, in this study, we investigated the effects of quercetin on EMT of SRA01/04 and high-glucose (HG)-induced lens opacity accompanied by lens fibrosis induced by type-1 diabetes. Furthermore, we sought to clarify the specific mechanisms underlying these effects. At week 14 after streptozotocin (STZ) intraperitoneal administration, diabetic rats showed lens opacity accompanied with diminished antioxidant function, enhanced polyol pathway activity, and non-enzymatic glycation. Western blotting confirmed EMT in rat SRA01/04 cells with significantly increased α-smooth muscle actin (α-SMA) and decreased E-cadherin expressions. Treatment of the lens with quercetin ameliorated the oxidative stress, inhibited aldose reductase (AR) activation, reduced advanced glycation end product (AGE) production, and finally suppressed EMT in the early stages. Our in vitro results showed that high-glucose activated the transforming growth factor-β2/phosphoinositide 3-kinase/protein kinase B (TGF-β2/PI3K/Akt) signalling and EMT in SRA01/04 cells. Further, induced oxidative stress, activation of aldose reductase, and accumulation of advanced glycation end products were also involved in this process. Quercetin was potent enough to effectively ameliorate the high glucose (HG)-induced EMT of SRA01/04 cells by inhibiting the activation of TGF-β2/PI3K/Akt, enhancing the antioxidant capacity, inhibiting AR activity, and reducing AGE production. From the whole animal to tissues, and finally the cellular level, our results provide considerable evidence of the therapeutic potential of quercetin for DC. This might be due to its inhibition of EMT mediated through inhibition of the TGF-β/PI3K/Akt pathway.

Thalamic amplification of sensory input in experimental diabetes.

Diabetic neuropathy is a common, and often debilitating, secondary complication of diabetes mellitus. As pain, hypersensitivity and paraesthesias present in a distal–proximal distribution, symptoms are generally believed to originate from damaged afferents within the peripheral nervous system. Increasing evidence suggests altered processing within the central nervous system in diabetic neuropathy contributes towards somatosensory dysfunction, but whether the accurate coding and relay of peripherally encoded information through the central nervous system is altered in diabetes is not understood. Here, we applied the strengths of the rodent whisker–barrel system to study primary afferent‐thalamic processing in diabetic neuropathy. We found that neurons in the thalamic ventral posteromedial nucleus from rats with experimental diabetic neuropathy showed increased firing to precisely graded, multidirectional whisker deflection compared to non‐diabetic rats. This thalamic hyperactivity occurred without any overt primary afferent dysfunction, as recordings from the trigeminal ganglion showed these primary afferents to be unaffected by diabetes. These findings suggest that central amplification can substantially transform ascending sensory input in diabetes, even in the absence of a barrage of ectopic primary afferent activity.

SYNTHESIS AND EVALUATION OF SOME NEW 2-(5-(4-BENZAMIDOBENZYLIDENE)-2,4DIOXOTHIAZOLIDIN-3-YL)ACETIC ACID ANALOGS AS ALDOSE REDUCTASE INHIBITORS

ABSTRACTObjective: Aldose reductase (ALR) enzyme plays a significant role in conversion of excess amount of glucose into sorbitol in diabetic condition,inhibitors of which decrease the secondary complication of diabetes mellitus. Scarce treatment of diabetic complications has motivated our interestfor the search of new aldose reductase inhibitors (ARIs) endowed with more favorable biological properties.Methods: Newer (4-(benzamidobenzylidene)-2,4-dioxothiazolidin-3-yl) acetic acid derivatives were synthesized, and these compound wereevaluated for their ARI and antidiabetic activity.Results: ARI activity of synthesized compounds was found in the range of 57.8-71.9% at 5µg/mL. Similarly, synthesized compounds decrease bloodglucose level in the range of 64.4-70.5 mg/dl at 15 mg/kg body weight.Conclusion: (E)-2-(5-(4-(substituted benzamido)benzylidene)-2,4-dioxothiazolidin-3-yl)acetic acid analogs shows comparable ARI as well asantidiabetic activity. These new class of compounds might be address the diabetic complications with safety.Keywords: Aldose reductase inhibitors, Diabetes mellitus, N-acetic acid-2,4-thiazolidinediones.

Evaluation of the quality of life in Brazilian diabetic patients: comparison between specific and generic free instruments

The aim of this study was to compare two free tools, the specific Diabetes Quality of Life Measure (DQOL) and the generic Nottingham Health Profile (NHP), which measure the health-related quality of life (HRQL), in Brazilian patients with diabetes mellitus (DM). The DQOL and NHP were administered to 150 adult patients with type 1 diabetes mellitus (DM1) and 146 adult patients with type 2 (DM2). The scores were compared with age, time since diagnosis of DM, glycated haemoglobin (A1c), insulin use and the presence of secondary complications; for patients with DM2, the Diabetes Complications Index (DCI) was also administered. Factor analysis demonstrated similarity in the principal distribution of components in the two instruments, and there were low to moderate correlations between their domains. The NHP was directly correlated with patient’s age. DQOL was directly correlated with time since diagnosis of DM and A1c levels. The NHP predicted secondary complications of DM1. Both instruments had a direct correlation with the DCI, but the results were more significant for the NHP. The impact of insulin use was better identified by the DQOL. The NHP does not replace the DQOL for quality of life assessment in diabetic patients. However, its usefulness is not limited to the comparison of HRQL perception between diabetic and nondiabetic patients because the NHP is more sensitive than the DQOL in evaluating the impact of secondary complications of DM on HRQL.

Design, synthesis and evaluation of rhodanine derivatives as aldose reductase inhibitors.

Aldose reductase (ALR) enzyme plays a significant role in conversion of excess amount of glucose into sorbitol in diabetic condition, inhibitors of which decrease the secondary complication of diabetes mellitus. To understand the structural interaction of inhibitors with ALR enzyme and develop more effective ALR inhibitors, a series of substituted 5-phenylbenzoate containing N-substituted rhodanine derivatives were synthesized and evaluated for their in vitro ALR inhibitory activity. Docking studies of these compounds were carried out, which revealed that the 5-phenylbenzoate moiety deeply influenced the key π-π stacking while 4-oxo-2-thioxothiazolidines contributed in hydrogen bond interactions. The phenyl ring of benzylidene system occupied in specific pocket constituted from Phe115, Phe122, Leu300 and Cys303 while the rhodanine ring forms a tight net of hydrogen bond with Val47 at anionic binding site of the enzyme. The structural insights obtained from the docking study gave better understanding of rhodanine and macromolecular interaction and will help us in further designing and improving of ALR inhibitory activity of rhodanine analogs.

Mesenchymal stem cell-based treatment for microvascular and secondary complications of diabetes mellitus.

The worldwide increase in the prevalence of Diabetes mellitus (DM) has highlighted the need for increased research efforts into treatment options for both the disease itself and its associated complications. In recent years, mesenchymal stromal cells (MSCs) have been highlighted as a new emerging regenerative therapy due to their multipotency but also due to their paracrine secretion of angiogenic factors, cytokines, and immunomodulatory substances. This review focuses on the potential use of MSCs as a regenerative medicine in microvascular and secondary complications of DM and will discuss the challenges and future prospects of MSCs as a regenerative therapy in this field. MSCs are believed to have an important role in tissue repair. Evidence in recent years has demonstrated that MSCs have potent immunomodulatory functions resulting in active suppression of various components of the host immune response. MSCs may also have glucose lowering properties providing another attractive and unique feature of this therapeutic approach. Through a combination of the above characteristics, MSCs have been shown to exert beneficial effects in pre-clinical models of diabetic complications prompting initial clinical studies in diabetic wound healing and nephropathy. Challenges that remain in the clinical translation of MSC therapy include issues of MSC heterogeneity, optimal mode of cell delivery, homing of these cells to tissues of interest with high efficiency, clinically meaningful engraftment, and challenges with cell manufacture. An issue of added importance is whether an autologous or allogeneic approach will be used. In summary, MSC administration has significant potential in the treatment of diabetic microvascular and secondary complications but challenges remain in terms of engraftment, persistence, tissue targeting, and cell manufacture

Contribution of PON1 Polymorphism in Senile Cataract among Diabetic and Non-Diabetic Egyptian Patients

Background: The development of senile cataract is a multifactorial process with oxidative stress and its sequelae are clearly involved in its etiology. Cataract is also one of the earliest secondary complications of diabetes mellitus. Paraoxonase (PON) enzyme is an antioxidant High-Density Lipoprotein (HDL)-associated enzyme. In mammals, three genes of paraoxonase, PON1, PON2, and PON3, have been identified. Aim: To assess the contribution of PON1-55 and PON1-192 gene polymorphisms as risk factors for senile cataract formation among diabeticand non-diabetic Egyptian patients. Methods: 132 Egyptian cataract patients (66 without diabetes and 66 with diabetes) and 106 subjects with matched age and sex free of cataract and diabetes control subjects were included in the present study using multiplex PCR for PON1-55 and PON1-192 gene polymorphisms followed by restriction fragment length polymorphism analysis. Results: The study revealed that there was a significant difference in PON1-55 genotypes; LL, LM and MM (p=0.0001) and in PON1-192 genotypes; QQ, QR and RR (p=0.0001) genotypes distribution among cataract patients with and without diabetes and controls. Also there was a significant difference in L and M (p=0.003) and in Q and R allele frequencies (p=0.005) among cataract patients with and without diabetes and controls. In addition there was a significant difference in the distribution of 55 LM/192 RR combined genotypes with the highest frequency in cataract diabetic subgroup (75%), while 55LL/192RR, 55LL/192QR and 55LM/192QR combined genotypes showed the highest frequencies among the control group (52.4%, 59.1% and 66.7% respectively). Conclusion: For the first time, we provide evidence that functional polymorphisms in the PON1 gene may influence the risk of cataract in both non-diabetic and diabetic subgroups in Egyptian populations, suggesting new clues that help to clarify the pathogenesis of cataract.

Renoprotective Effect ofCoccinia indicaFruits and Leaves in Experimentally Induced Diabetic Rats

Diabetic nephropathy is one of the secondary complications of diabetes mellitus that is marked by changes in extracellular matrix components leading to end-stage renal failure. Diet plays an important role in managing diabetes. In the present study, the effect of Coccinia indica consumption on diabetes-mediated kidney damage was determined. Both control and diabetic rats were fed with AIN-76 diet supplemented with C. indica fruits and leaves individually at 10% and 5%, respectively, for a period of 2 months. Various parameters, such as fasting blood glucose, urine sugar, albumin excretion, kidney index, and glomerular filtration rate, were ameliorated to various extents by the supplementation of C. indica in the diet. Additionally, diabetic rats fed with diet supplemented with C. indica fruits or leaves showed improvement in glucose tolerance compared to control diabetic rats. They also exhibited beneficial effects on key antioxidant enzymes of the kidney. Furthermore, an increase in laminin and fibronectin as a result of diabetes was alleviated in C. indica-fed rats. These results indicate that the consumption of C. indica is beneficial in partially containing diabetes-mediated deleterious effects on the kidney.

Inhibition of sorbitol dehydrogenase by nucleosides and nucleotides

Sorbitol dehydrogenase inhibitors have been found to prevent, or alleviate, various secondary complications of diabetes mellitus. In the present study, the effects of nucleosides and nucleotides on the rate of sorbitol oxidation catalyzed by the sheep liver enzyme were studied by steady-state kinetics at pH 7.4. Various such compounds, including ATP and the 2′-deoxy-analogues of ATP, ADP and AMP, reversibly inhibit enzyme activity by formation of enzyme–coenzyme-inhibitor ternary complexes. In each case, no deviations from linearity were seen in the double-reciprocal plots using sorbitol or NAD+ as the varied substrate and there was a linear relationship between inhibitor concentration and the observed inhibitory effects. Sorbitol was docked into a model of the sheep SDH-NAD+ complex based upon the structure of the human SDH-NAD+ holoenzyme. The resulting structure of the ternary complex of sheep SDH, NAD+ and sorbitol (PMDB ID code PM 0078068) shows that the reactive C-2 hydroxyl group of sorbitol is oriented toward the 4′-position of the nicotinamide moiety of the coenzyme, and that the adjacent primary hydroxyl group of sorbitol interacts with the catalytic zinc. The results indicate that the ribose moiety of the inhibitor structures is an important determinant for the observed effects. Specifically, the 2′-position of the ribose ring exerts an effect with respect to inhibitor potency.