Zinc deficient diet exacerbates the testicular and epididymal damage in type 2 diabetic rat: Studies on oxidative stress-related mechanisms

Zinc (Zn) is one of the most important trace elements in the body and is required for insulin secretion and release. Zn is also required for the growth and development of the reproductive system. Alteration in the Zn levels can cause moderate to severe damage to various organs, including the reproductive system. Most of type 2 diabetic patients have altered Zn levels/signaling. So, here we investigated the role of Zn-deficient diet (ZDD) in type 2 diabetes. Type 2 diabetes in the rat was induced by the combination of high-fat diet (HFD) and a single low dose of streptozotocin (STZ, 35 mg/kg, i.p.). Control animals were fed normal pellet diet throughout the study, while ZDD was given for four consecutive weeks to the diabetic rats, which were earlier kept on HFD for 16 weeks. The present findings showed that ZDD further decreased the serum Zn, plasma insulin and serum testosterone levels, whereas it increased cholesterol, triglycerides, BUN, %HbA1c in diabetic rats. Oxidative stress in testes was increased by ZDD as evidenced by decreased glutathione, catalase and SOD1 levels. ZDD-induced several abnormalities in sperm head morphology, altered sperm decondensation, sperm chromatin and protamine content, along with significant histopathological alterations in testes and epididymis. Further, ZDD altered protein levels of MT, MTF-1, Keap1, Nrf2, Nf-κB, GPX4 and GPX5 levels in the testes and epididymis of diabetic rat. The present results demonstrated that dietary Zn deficiency could exacerbate type 2 diabetes-induced germ cell damage.     

Hyperglycemia-induced oxidative stress in diabetic complications

Reactive oxygen species are increased by hyperglycemia. Hyperglycemia, which occurs during diabetes (both type 1 and type 2) and, to a lesser extent, during insulin resistance, causes oxidative stress. Free fatty acids, which may be elevated during inadequate glycemic control, may also be contributory. In this review, we will discuss the role of oxidative stress in diabetic complications. Oxidative stress may be important in diabetes, not just because of its role in the development of complications, but because persistent hyperglycemia, secondary to insulin resistance, may induce oxidative stress and contribute to beta cell destruction in type 2 diabetes. The focus of this review will be on the role of oxidative stress in the etiology of diabetic complications.     

Mitochondrial dysfunction and complications associated with diabetes

Background

Diabetes is a metabolic syndrome that results in chronically increased blood glucose (hyperglycaemia) due to defects either in insulin secretion consequent to the loss of beta cells in the pancreas (type 1) or to loss of insulin sensitivity in target organs in the presence of normal insulin secretion (type 2). Long term hyperglycaemia can lead to a number of serious health-threatening pathologies, or complications, especially in the kidney, heart, retina and peripheral nervous system.

Scope of review

Here we summarise the current literature on the role of the mitochondria in complications associated with diabetes, and the limitations and potential of rodent models to explore new modalities to limit complication severity.

Major conclusions

Prolonged hyperglycaemia results in perturbation of catabolic pathways and in an over-production of ROS by the mitochondria, which in turn may play a role in the development of diabetic complications. Furthermore, current models don't offer a comprehensive recapitulation of these complications.

General significance

The onset of complications associated with type 1 diabetes can be varied, even with tightly controlled blood glucose levels. The potential role of inherited, mild mitochondrial dysfunction in accelerating diabetic complications, both in type 1 and 2 diabetes, remains unexplored. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes

Insulin resistance is a primary characteristic of type 2 diabetes and likely causally related to the pathogenesis of the disease. It is a result of defects in signal transduction from the cell surface receptor of insulin to target effects. We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. EC(50) for insulin-stimulated phosphorylation of serine 307 was about 0.2 nM with a t(1/2) of about 2 min. The amount of IRS1 was similar in cells from non-diabetic and diabetic subjects. These findings identify a molecular mechanism for insulin resistance in non-selected patients with type 2 diabetes.     

Fetal cardiac effects of maternal hyperglycemia during pregnancy

Maternal diabetes mellitus is associated with increased teratogenesis, which can occur in pregestational type 1 and type 2 diabetes. Cardiac defects and with neural tube defects are the most common malformations observed in fetuses of pregestational diabetic mothers. The exact mechanism by which diabetes exerts its teratogenic effects and induces embryonic malformations is unclear. Whereas the sequelae of maternal pregestational diabetes, such as modulating insulin levels, altered fat levels, and increased reactive oxygen species, may play a role in fetal damage during diabetic pregnancy, hyperglycemia is thought to be the primary teratogen, causing particularly adverse effects on cardiovascular development. Fetal cardiac defects are associated with raised maternal glycosylated hemoglobin levels and are up to five times more likely in infants of mothers with pregestational diabetes compared with those without diabetes. The resulting anomalies are varied and include transposition of the great arteries, mitral and pulmonary atresia, double outlet of the right ventricle, tetralogy of Fallot, and fetal cardiomyopathy. A wide variety of rodent models have been used to study diabetic teratogenesis. Both genetic and chemically induced models of type 1 and 2 diabetes have been used to examine the effects of hyperglycemia on fetal development. Factors such as genetic background as well as confounding variables such as obesity appear to influence the severity of fetal abnormalities in mice. In this review, we will summarize recent data on fetal cardiac effects from human pregestational diabetic mothers, as well as the most relevant findings in rodent models of diabetic cardiac teratogenesis. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Stem cell-based therapies and immunomodulatory approaches in newly diagnosed type 1 diabetes

Type 1 diabetes mellitus is an autoimmune disease against pancreatic β cells. The autoimmune response begins months or years before the clinical presentation. At the time of hyperglycemic symptoms a small amount of β cell mass still remains. The main therapeutic option to type 1 diabetes mellitus is daily insulin injections which is shown to promote tighter glucose control and to reduce much of diabetic chronic complications. Subgroup analysis of the Diabetes Control and Complication Trial (DCCT) showed another important aspect related to long term complications of diabetes, ie, patients with initially larger residual β cell mass suffered less microvascular complications and less hypoglycemic events than those patients with small amounts of β cells at diagnosis. In face of this, β cell preservation has become another important target in the management of type 1 diabetes and its related complications. In this review, we summarize various immunomodulatory regimens ever used in humans, including stem cell-based strategies, aiming at blocking autoimmunity against pancreatic β cells and at promoting β cell preservation and/or possible β cell regeneration in recent-onset type 1 diabetes.     

FGF1:一种治疗糖尿病的新型潜在药物

糖尿病是一种常见的内分泌代谢性疾病,它及其并发症的治疗是现代医学仍未解决的难题。常见的药物治疗有诸多不良反应,譬如胰岛素的长期使用会产生胰岛素耐受性。近年研究发现,酸性成纤维细胞因子（Fibroblast growth factor 1,FGF1或aFGF）及其衍生物能够使2型糖尿病小鼠的血糖快速恢复至正常水平,并且具有胰岛素增敏效果,规避了胰岛素治疗产生耐受性的问题。因此,人们对FGF1及其衍生物在开发新型T2DM疗法方面给予诸多期待。该综述系统介绍了FGF1的结构与功能、降糖功效的机制及新发现,对FGF1的2种注射方式和FGF家族在降糖作用方面进行了比较,并对FGF1在治疗糖尿病方面的研究进程进行展望,旨在为调节血糖、解决胰岛素耐受性问题提供一种新的思路和方法。     

Endothelial progenitor cells in diabetes mellitus

Diabetes mellitus is associated with an increased risk of cardiovascular disease due to its negative impact on the vascular endothelium. The damaged endothelium is repaired by resident cells also through the contribution of a population of circulating cells derived from bone marrow. These cells, termed endothelial progenitor cells (EPCs) are involved in maintaining endothelial homeostasis and contributes to the formation of new blood vessels with a process called postnatal vasculogenesis. The mechanisms whereby these cells allow for protection of the cardiovascular system are still unclear; nevertheless, consistent evidences have shown that impairment and reduction of EPCs are hallmark features of type 1 and type 2 diabetes. Therefore, EPC alterations might have a pathogenic role in diabetic complications, thus becoming a potential therapeutic target. In this review, EPC alterations will be examined in the context of macrovascular and microvascular complications of diabetes, highlighting their roles and functions in the progression of the disease.     

Is insulin an anabolic agent in bone? Dissecting the diabetic bone for clues

Diabetic osteoporosis is increasingly recognized as a significant comorbidity of type 1 diabetes mellitus. In contrast, type 2 diabetes mellitus is more commonly associated with modest increases in bone mineral density for age. Despite this dichotomy, clinical, in vivo, and in vitro data uniformly support the concept that new bone formation as well as bone microarchitectural integrity are altered in the diabetic state, leading to an increased risk for fragility fracture and inadequate bone regeneration following injury. In this review, we examine the contribution that insulin, as a potential anabolic agent in bone, may make to the pathophysiology of diabetic bone disease. Specifically, we have assimilated human and animal data examining the effects of endogenous insulin production, exogenous insulin administration, insulin sensitivity, and insulin signaling on bone. In so doing, we present evidence that insulin, acting as an anabolic agent in bone, can preserve and increase bone density and bone strength, presumably through direct and/or indirect effects on bone formation.     

Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications

In addition to a number of deleterious effects on cellular integrity and functions, diabetic metabolic milieu has been implicated in a rapidly growing number of alterations in signal transduction. In this review we focus on Akt kinase physiology, its alterations in diabetes mellitus (DM), and on the emerging role of this signaling system in the pathophysiology of diabetic microvascular complications. Studies focusing on Akt in diabetes suggest both decrease and increase of Akt activity in DM. Alterations of Akt activity have been found in various tissues and cells in diabetes depending on experimental and clinical contexts. There is convincing evidence suggesting defective Akt signaling in the development of insulin resistance. Similar defects, as in insulin-sensitive tissues, have been reported in endothelia of DM Type 2 models, possibly contributing to the development of endothelial dysfunction under these conditions. In contrast, Akt activity is increased in some tissues and vascular beds affected by complications in DM Type 1. Identification of the role of this phenomenon in DM-induced growth and hemodynamic alterations in affected vascular beds remains one of the major challenges for future research in this area. Future studies should include the evaluation of therapeutical benefits of pharmacological modulators of Akt activity.     

上皮细胞离子通道对雌性生殖道内液体微环境的调节作用:对生殖与不孕的影响

雌性生殖道内适宜的液体微环境对一系列生殖事件起至关重要的作用。位于生殖道上皮细胞顶膜或基底膜的一系列离子通道和转运体,通过对水、电解质的跨膜转运,从而调节雌性生殖道内液体的分泌与吸收。本综述着重探讨了上皮细胞钠离子通道和囊性纤维化跨膜电导调节体对雌性生殖道内液体容量和成分的调节以及它们在不同生殖事件,比如精子获能及着床中的重要作用。同时对因离子通道失活或失调引起的雌性生殖道内液体微环境稳态失衡导致的一系列病理改变,如卵巢过度刺激综合征、输卵管积水以及不孕提出了新的见解。     

New Insights into Bioactive Compounds of Traditional Chinese Medicines for Insulin Resistance Based on Signaling Pathways

Type 2 diabetes is a serious metabolic disease as a long‐term threat to human health. Insulin resistance is not only the basis and major feature of type 2 diabetes, but also the main etiology of diseases such as hypertension, hyperlipidemia and coronary heart disease. It has been shown that Traditional Chinese Medicines (TCMs) play an important role in the treatment of type 2 diabetes, through attenuating insulin resistance, whereas the mechanism involved is not yet well understood. Therefore, it is important to elucidate the pharmacological mechanism of these bioactive compounds so that one can pave the way for the modernization of TCMs. In this review, we focus on the recent progresses of some bioactive ingredients from TCMs with different functional groups, which exhibit therapeutic potential for the treatment of diabetic insulin resistance. It is expected that this review can provide new references for developing TCM‐derived drugs against diabetes and insulin resistance in the future.     

Maternal diabetes and oocyte quality

Maternal diabetes has been demonstrated to adversely affect preimplantation embryo development and pregnancy outcomes. Emerging evidence has implicated that these effects are associated with compromised oocyte competence. Several developmental defects during oocyte maturation in diabetic mice have been reported over past decades. Most recently, we further identified the structural, spatial and metabolic dysfunction of mitochondria in oocytes from diabetic mice, suggesting the impaired oocyte quality. These defects in the oocyte may be maternally transmitted to the embryo and then manifested later as developmental abnormalities in preimplantation embryo, congenital malformations, and even metabolic disease in the offspring. In this paper, we briefly review the effects of maternal diabetes on oocyte quality, with a particular emphasis on the mitochondrial dysfunction. The possible connection between dysfunctional oocyte mitochondria and reproductive failure of diabetic females, and the mechanism(s) by which maternal diabetes exerts its effects on the oocyte are also discussed.     

1型糖尿病的基因治疗进展

尽管皮下注射胰岛素、口服降糖药等可以缓解糖尿病患者的高血糖,但是这些治疗措施只是暂时性的,并不能从根本上彻底治疗糖尿病以及阻止其他并发症的发生。随着人们对糖尿病本质的深层次揭示和现代分子生物学手段的发展,针对由胰岛素分泌缺乏引起的1型糖尿病(T1D)基因治疗手段逐渐丰富。总结了胰岛素替代基因的直接导入,刺激新的β细胞再生以及阻止胰岛β细胞的自身免疫,抑制胰岛β细胞的凋亡等1型糖尿病的基因治疗新进展,并展望其未来发展方向。     

Effects of larval exposure to sublethal concentrations of the ecdysteroid agonists RH-5849 and tebufenozide (RH-5992) on male reproductive physiology in Spodoptera litura

Sublethal concentrations of the bisacylhydrazine moulting hormone agonists, RH-5849, and tebufenozide (RH-5992) were fed to sixth (final) instar larvae of Spodoptera litura. Both RH-5849 and tebufenozide adversely affected the mating success of S. litura when the surviving treated males were crossed with normal females. The ecdysone agonists decreased the longevity of treated males and of untreated females when crossed with treated males. The number of eggs laid by untreated females mated to treated males was decreased, and the fertility (percentage of hatching success) of the resulting eggs was reduced. These effects on male reproductive success were at least in part explained by a reduction in the number of sperm transferred during mating. The adverse effects of tebufenozide on male reproductive function were qualitatively the same as those of RH-5849, but tebufenozide was active at lower concentrations. To understand the reason for these adverse effects on male reproduction, we investigated the effects of the insecticides on male reproductive physiology. Male reproductive tract development and testicular volume of resulting adult moths were adversely affected by sublethal larval exposure to the ecdysone agonists. Dose-dependent reductions occurred in the production of eupyrene and apyrene spermatozoa in the adult testes, and in the number of spermatozoa released from the testes into the male reproductive tract. The descent into the male tract of both eupyrene and apyrene sperm was found to start at the normal stage of development in both normal and treated insects, but the daily rhythm of sperm descent was subsequently disturbed in the insecticide-treated moths. This affected the numbers of sperm in the upper vas deferens (UVD), seminal vesicle (SV), and duplex (duplex). Injections of RH-5849 given to pharate adult or newly emerged adult S. litura also caused drastic reduction in the number of sperm in the upper regions of the male tract, when measured 24 h after injection. The possible importance of pest population reduction through the sublethal anti-reproductive effects of insecticides is discussed.     

胞外ATP在男性生殖道中的作用

胞外ATP除了能广泛作为神经递质外,还被认为是一种旁分泌或自分泌因子。ATP从男性生殖道中的精子或上皮细胞中释放,在调节各种生殖生理功能中起多种作用。本文综述了ATP调节附睾上皮细胞阴离子分泌的信号通路,阐述了ATP对依赖上皮细胞的输精管平滑肌收缩的调节机制,讨论了ATP在男性生殖道中的功能和作用。     

Inhibition of PKCepsilon improves glucose-stimulated insulin secretion and reduces insulin clearance

In type 2 diabetes, pancreatic beta cells fail to secrete sufficient insulin to overcome peripheral insulin resistance. Intracellular lipid accumulation contributes to beta cell failure through poorly defined mechanisms. Here we report a role for the lipid-regulated protein kinase C isoform PKCepsilon in beta cell dysfunction. Deletion of PKCepsilon augmented insulin secretion and prevented glucose intolerance in fat-fed mice. Importantly, a PKCepsilon-inhibitory peptide improved insulin availability and glucose tolerance in db/db mice with preexisting diabetes. Functional ablation of PKCepsilon selectively enhanced insulin release ex vivo from diabetic or lipid-pretreated islets and optimized the glucose-regulated lipid partitioning that amplifies the secretory response. Independently, PKCepsilon deletion also augmented insulin availability by reducing both whole-body insulin clearance and insulin uptake by hepatocytes. Our findings implicate PKCepsilon in the etiology of beta cell dysfunction and highlight that enhancement of insulin availability, through separate effects on liver and beta cells, provides a rationale for inhibiting PKCepsilon to treat type 2 diabetes.     

Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells

Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPARgamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPARgamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPARgamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.