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1.
糖尿病是骨质疏松性骨折的危险因素之一,无论是 1 型还是 2 型糖尿病患者,其发生骨质疏松症和糖尿病性骨折的风险均显著升高。研究表明,糖尿病患者骨转换指标明显低于正常人群,尤其是骨形成动力不足。目前针对糖尿病合并骨质疏松症患者的抗骨质疏松治疗尚无明确的指南。抗骨质疏松症药物尤其是抗骨吸收药物,可进一步降低骨转换,同时,其可能影响骨钙素(osteocalcin,OC)等细胞因子的分泌从而对糖代谢产生不利影响。而目前许多动物实验及临床研究发现,常用抗骨质疏松症药物用于糖尿病患者不仅有抗骨质疏松作用,甚至可能对糖代谢产生积极影响。本文通过综述抗骨质疏松症药物对糖尿病患者糖代谢及骨代谢的影响,旨在为糖尿病患者抗骨质疏松治疗及避免糖尿病性骨折的发生提供有效的参考。  相似文献   

2.
Growth hormone (GH) and IGFs have a long distinguished history in diabetes, with possible participation in the development of renal complications. The implicated effect of GH in diabetic end-stage organ damage may be mediated by growth hormone receptor (GHR) or postreceptor events in GH signal transduction. The present study investigates the effects of diabetes induced by streptozotocin (STZ) on renal GH signaling. Our results demonstrate that JAK2, insulin receptor substrate (IRS)-1, Shc, ERKs, and Akt are widely distributed in the kidney, and after GH treatment, there is a significant increase in phosphorylation of these proteins in STZ-induced diabetic rats compared with controls. Moreover, the GH-induced association of IRS-1/phosphatidylinositol 3-kinase, IRS-1/growth factor receptor bound 2 (Grb2), and Shc/Grb2 are increased in diabetic rats as well. Immunohistochemical studies show that GH-induced p-Akt and p-ERK activation is apparently more pronounced in the kidneys of diabetic rats. Administration of G120K-PEG, a GH antagonist, in diabetic mice shows inhibitory effects on diabetic renal enlargement and reverses the alterations in GH signal transduction observed in diabetic animals. The present study demonstrates a role for GH signaling in the pathogenesis of early diabetic renal changes and suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.  相似文献   

3.
Myocardial contractile responses to halothane, enflurane, and isoflurane were studied in papillary muscles isolated from streptozotocin-induced diabetic rats and in those from age-matched control rats. The developed tension in diabetic papillary muscles electrically paced at a constant rate was not different from that in control muscles, but both the time to peak tension and the relaxation time of the isometric contraction were significantly prolonged in diabetic muscles. Halothane, enflurane, and isoflurane all produced negative inotropic effects in both diabetic and control muscles. However, the negative inotropic effects were significantly less in the muscles from diabetic rats than in the muscles from control rats throughout the range of concentrations. In muscles from both the diabetic and control rats, the negative inotropic effects of these anesthetics were accompanied by decreases in the time to peak tension and in relaxation time. The results suggest that the myocardium from the diabetic rat is less sensitive to the negative inotropic action of volatile anesthetics than is the myocardium of normal hearts.  相似文献   

4.
Advanced glycation end products (AGEs) are involved in the development of microvascular complications, including alterations of retinal pericyte and renal mesangial cell growth occurring during diabetic retinopathy and diabetic nephropathy, respectively. Because gangliosides are implicated in the regulation of cell proliferation, we hypothesized that AGEs could exert cellular effects in part by modulating ganglioside levels. Results of the present study indicate that AGEs caused an inhibition of both bovine retinal pericyte (BRP) and rat renal mesangial cell (RMC) proliferation, associated with an increase of a-series gangliosides consecutive to GM3 synthase activity increase and GD3 synthase activity inhibition. Similar modifications were also found in the renal cortex of diabetic db/db mice compared with controls. Treatment of BRP and RMC with exogenous a-series gangliosides decreased proliferation and blockade of a-series gangliosides with specific antibodies partially protecting the two cell types from the AGE-induced proliferation decrease. Further, inhibition of GM3 synthase using specific SiRNA partially reversed the AGE effects on mesangial cell proliferation. These results suggest that a-series gangliosides are mediators of the adverse AGE effects on BRP and RMC proliferation. They also raise the hypothesis of common mechanisms involved in the development of diabetic retinopathy and diabetic nephropathy.  相似文献   

5.
牛磺酸对糖尿病大鼠肾脏氧化应激和非酶糖基化的抑制作用   总被引:11,自引:0,他引:11  
目的 研究牛磺酸对糖尿病大鼠肾脏氧化应激反应和非酶糖基化的抑制效果。方法 链脲佐菌素诱发的糖尿病大鼠用牛磺酸治疗14 周后,评价牛磺酸对糖尿病大鼠肾脏氧自由基代谢和非酶糖基化产物的影响。结果 与对照组大鼠比较,糖尿病大鼠肾皮质超氧化物岐化酶(SOD)和过氧化氢酶(CAT) 活性明显降低,而丙二醛含量明显增加;血清和肾皮质晚期糖基化终末产物(AGEs) 水平升高和肾小球AGEs 的形成增加。牛磺酸治疗可明显增加糖尿病大鼠肾脏SOD 和CAT活性,减低肾皮质MDA含量,显著降低糖尿病大鼠血清、肾脏AGEs 水平,减少肾小球AGEs 的形成。结论 牛磺酸能明显抑制糖尿病大鼠肾脏氧化应激反应和非酶糖基化。  相似文献   

6.
A Ghahary  S Chakrabarti  A A Sima  L J Murphy 《Diabetes》1991,40(11):1391-1396
Tissue accumulation of sorbitol secondary to enhanced polyol-pathway activity is believed to play an important role in the development of diabetic complications. We previously demonstrated sorbitol accumulation, due in part to enhanced expression of aldose reductase (AR) in the diabetic kidney. In this study, we quantitated AR enzyme activity, immunoreactivity, and mRNA in various tissues from nondiabetic and diabetic BB/Wor rats 3 mo after onset of diabetes. In addition, the effects of intensive insulin treatment (3-6 U/day) and the effects of the AR inhibitor Statil (25 mg.kg-1.day-1) on AR expression were determined. Of 13 tissues examined, AR activity was significantly increased in the lens, kidney, sciatic nerve, skeletal muscle, retina, and spinal cord from diabetic rats compared with age-matched nondiabetic control rats. In most tissues, AR immunoreactivity and AR mRNA were proportionately elevated. Intensive insulin treatment, which normalized blood glucose and glycosylated hemoglobin, significantly reduced AR activity and immunoreactivity. AR mRNA abundance was also reduced in tissues from insulin-treated diabetic rats. Statil treatment had no significant effect on AR immunoreactivity or AR mRNA abundance, although AR activity in tissues from Statil-treated diabetic rats was significantly reduced compared with untreated diabetic rats. These studies demonstrate that the expression of the AR gene is upregulated in most tissues of the diabetic rat, that insulin treatment reverses this phenomenon, and that AR inhibition has no effect on AR gene expression.  相似文献   

7.
Diabetic nephropathy is characterized by progressive loss of renal function, persistent proteinuria, and relentless accumulation of extracellular matrix leading to glomerulosclerosis and interstitial fibrosis. This study investigated the potential effects of long-term expression of exogenous hepatocyte growth factor (HGF) on normal and diabetic kidneys. Intravenous injection of human HGF gene via naked plasmid vector resulted in abundant HGF protein specifically localized in renal glomeruli, despite an extremely low level of transgene mRNA in the kidney. In uninephrectomized mice made diabetic with streptozotocin, delivery of exogenous HGF gene ameliorated the progression of diabetic nephropathy. HGF attenuated urine albumin and total protein excretion in diabetic mice. Exogenous HGF also mitigated glomerular mesangial expansion, reduced fibronectin and type I collagen deposition, and prevented interstitial myofibroblast activation. In addition, HGF prevented kidney cells from apoptotic death in the glomeruli and tubulointerstitium. Moreover, expression of HGF inhibited renal expression of TGF-beta1 and reduced urine level of TGF-beta1 protein. Therefore, despite the effects of HGF on diabetic nephropathy being controversial, these observations suggest that supplementation of HGF is beneficial in ameliorating diabetic renal insufficiency in mice.  相似文献   

8.
9.
《Renal failure》2013,35(6):925-928
Abstract

To date, case–control studies on the association between a single-nucleotide polymorphism (SNP), rs2268388, in the acetyl-coenzyme A carboxylase beta (ACACB) gene and diabetic nephropathy have provided controversial results. To clarify the effect of rs2268388 on the risk of diabetic nephropathy, a meta-analysis of all case–control studies was performed. The fixed effects and random effects models showed that the C allele was associated with a decreased susceptibility risk of diabetic nephropathy compared with the T allele among Caucasian patients with diabetes. The contrast of the recessive model produced the same pattern of results as the allele contrast. Our pooled data suggest a significant association exists between rs2268388 and diabetic nephropathy among Caucasian patients with diabetes.  相似文献   

10.
Role of lipid control in diabetic nephropathy   总被引:4,自引:0,他引:4  
Patients with diabetic nephropathy are known to be associated with many lipoprotein abnormalities, including higher plasma levels of very low-density lipoprotein, low-density lipoprotein and triglycerides, and lower levels of high-density lipoprotein. Many studies have reported that lipids may induce both glomerular and tubulointerstitial injury through mediators such as cytokines, reactive oxygen species, chemokines, and through hemodynamic changes. Clinical studies in patients with diabetic nephropathy showed that lipid control can be associated with an additional effect of reduction in proteinuria. Experimental studies demonstrated that lipid-lowering agents exerted a certain degree of renoprotection, through both indirect effects from lipid lowering and a direct effect on cell protection. Therefore, lipid control appears to be important in the prevention and treatment of diabetic nephropathy. Diabetic nephropathy has become the leading cause of end-stage renal failure in many countries, including Taiwan. One of the major risk factors for the development and progression of diabetic nephropathy is dyslipidemia. In this paper we will review the role of lipid in mediating renal injury and the beneficial effects of lipid control in diabetic nephropathy.  相似文献   

11.
Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy.  相似文献   

12.
Maternal diabetes and retarded preimplantation development of mice   总被引:1,自引:0,他引:1  
L F Beebe  P L Kaye 《Diabetes》1991,40(4):457-461
The streptozocin-induced diabetic (STZ-D) mouse was found to be a suitable model for studying the effects of maternal diabetes on the preimplantation embryo. This study looked at the effects of maternal diabetes on embryonic growth. Female Quakenbush mice were made diabetic (plasma glucose levels greater than 20 mM) by injection of 190 mg/kg i.p. STZ and were superovulated by standard methods. The blastocysts collected on day 4 from diabetic mothers had 8.5% fewer cells and a 35% lower protein synthetic rate than control embryos. Their cellular protein synthetic rate was 19% less than that in controls. Morulae from diabetic mothers also displayed a reduced protein synthetic rate, but this reduction was not seen in the two-cell embryo. Furthermore, blastocysts cultured in vitro from two-cell embryos from diabetic and control mothers displayed similar protein synthetic rates. This infers that the two-cell embryos from diabetic mothers are normal, and the retardation seen in later development in vivo occurs after the two-cell stage while the embryo is still free in the oviductal and uterine environment. Treatment of the diabetic mice with ultralente insulin every 12 h raised the protein synthetic rate of those blastocysts toward control levels, whereas treatment with lente insulin every 8 h recovered the embryo to the same rate as the control embryos. Because insulin has been shown to be mitogenic and stimulates protein synthesis of morulae and blastocysts in vitro, the absence of insulin in the diabetic mothers may be the cause of the retardation observed in their preimplantation embryos.  相似文献   

13.
SUMMARY Diabetic nephropathy is the commonest cause of end‐stage renal failure in the western world. It has been suggested that experimental models of diabetic nephropathy can be used to explore the natural history, pathogenesis and role of various treatments in this condition. Experimental diabetic nephropathy is associated with many but not all of the functional and structural abnormalities observed in human diabetic nephropathy, such as increased glomerular filtration rate, renal hypertrophy, albuminuria and glomerular and tubulointerstitial structural abnormalities. Diabetic nephropathy appears to occur as a result of an interplay of haemodynamic and metabolic factors. Haemodynamic factors include not only systemic and intraglomerular hypertension but also alterations in various vasoactive hormones and their receptors, which may act directly or via effects on blood pressure. Glucose dependent pathways have been implicated in diabetic nephropathy with recent studies focussing on advanced glycation end products and protein kinase C activation. Both glucose and haemodynamic dependent pathways activate a range of cytokines, including transforming growth factor‐β, which appear to play a pivotal role in mediating renal injury. Interventional studies in experimental models of diabetic nephropathy have emphasized the importance of tight glycaemic control and effective blood pressure reduction. In particular, agents that interrupt the renin–angiotensin system have been shown to be renoprotective but whether they are superior to other anti‐hypertensive agents has not been fully clarified. Experimental studies have provided the rationale for a number of clinical trials, which have confirmed the deleterious effects of hyperglycaemia and hypertension on the diabetic kidney. Experimental models of diabetic nephropathy are currently being used to explore more novel compounds which inhibit various pathogenic pathways implicated in the pathogenesis of diabetic nephropathy.  相似文献   

14.
Increased p38 mitogen-activated protein kinase (MAPK) in response to stress stimuli, including hyperglycemia, contributes to diabetic somatic neuropathy. However, effects on autonomic nerve and vascular function have not been determined. The aim of this study was to investigate the effects of the p38 MAPK inhibitor, LY2161793, on penile neurovascular function in streptozotocin-induced diabetic mice. Diabetes duration was 6 weeks and intervention LY2161793 treatment was given for the final 2 weeks. In vitro measurements on phenylephrine-precontracted corpus cavernosum revealed a 32% reduction in maximum nitrergic nerve-mediated relaxation with diabetes that was 74% corrected by LY2161793 treatment. Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was 42% attenuated by diabetes and 88% restored by LY2161793. Moreover, treatment partially corrected a diabetic deficit in endothelium-independent relaxation to a nitric oxide donor. Thus, p38 MAPK inhibition corrects nitric oxide-dependent indices of diabetic erectile autonomic neuropathy and vasculopathy, a therapeutic approach potentially worthy of consideration for clinical trials.  相似文献   

15.
This study aimed to assess the cavernous antioxidant effect of green tea (GT), epigallocatechin‐3‐gallate (EGCG) with/without sildenafil citrate intake in aged diabetic rats. One hundred and four aged male white albino rat were divided into controls that received ordinary chow, streptozotocin (STZ)‐induced aged diabetic rats, STZ‐induced diabetic rats on infused green tea, induced diabetic rats on epigallocatechin‐3‐gallate and STZ‐induced diabetic rats on sildenafil citrate added to EGCG. After 8 weeks, dissected cavernous tissues were assessed for gene expression of eNOS, cavernous malondialdehyde (MDA), glutathione peroxidase (GPx), cyclic guanosine monophosphate (cGMP), and serum testosterone (T). STZ‐induced diabetic rats on GT demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats. Diabetic rats on EGCG demonstrated significant increase in cavernous eNOS, cGMP, GPx and significant decrease in cavernous MDA compared with diabetic rats or diabetic rats on GT. Diabetic rats on EGCG added to sildenafil showed significant increase in cavernous eNOS, cGMP and significant decrease in cavernous MDA compared with other groups. Serum T demonstrated nonsignificant difference between the investigated groups. It is concluded that GT and EGCG have significant cavernous antioxidant effects that are increased if sildenafil is added.  相似文献   

16.
A serious consequence of diabetes mellitus is impaired wound healing, which largely resists treatment. We previously reported that topical application of calreticulin (CRT), an endoplasmic reticulum chaperone protein, markedly enhanced the rate and quality of wound healing in an experimental porcine model of cutaneous repair. Consistent with these in vivo effects, in vitro CRT induced the migration and proliferation of normal human cells critical to the wound healing process. These functions are particularly deficient in poor healing diabetic wounds. Using a genetically engineered diabetic mouse (db/db) in a full‐thickness excisional wound healing model, we now show that topical application of CRT induces a statistically significant decrease in the time to complete wound closure compared with untreated wounds by 5.6 days (17.6 vs. 23.2). Quantitative analysis of the wounds shows that CRT increases the rate of reepithelialization at days 7 and 10 and increases the amount of granulation tissue at day 7 persisting to day 14. Furthermore, CRT treatment induces the regrowth of pigmented hair follicles observed on day 28. In vitro, fibroblasts isolated from diabetic compared with wild‐type mouse skin and human fibroblasts cultured under hyperglycemic compared with normal glucose conditions proliferate and strongly migrate in response to CRT compared with untreated controls. The in vitro effects of CRT on these functions are consistent with CRT's potent effects on wound healing in the diabetic mouse. These studies implicate CRT as a potential powerful topical therapeutic agent for the treatment of diabetic and other chronic wounds.  相似文献   

17.
Studies indicate that hyperglycemia-induced oxidative stress triggers the development of microvascular and macrovascular complications in diabetes. Accordingly, we hypothesized that maslinic acid (MA) prevents these complications due to its antioxidant properties. We, therefore, investigated the effects of 5-week MA treatment of streptozotocin (STZ)-induced diabetic rats on anti-oxidative status of cardiac, hepatic and renal tissues as well as on kidney function. Proximal tubular effects of MA were studied in anesthetized rats challenged with hypotonic saline after a 3.5?h equilibration for 4 h of 1 h control, 1.5?h treatment and 1.5?h recovery periods using lithium clearance. MA was added to the infusate during the treatment period. Oral glucose tolerance responses to MA were monitored in rats given a glucose load after an 18?h fast. Compared with untreated diabetic rats, MA-treated diabetic animals exhibited significantly low malondialdehyde (MDA, a marker of lipid peroxidation) and increased the activity of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues. The expressions of gastrocnemius muscle GLUT4 and kidney GLUT1 and GLUT2 were assessed to elucidate the mechanism of the hypoglycemic effects of MA. MA-treatment diminished the expression of GLUT1 and GLUT2 in diabetic kidney and reduced glycemia values of diabetic rats. MA administration increased urinary Na+ outputs and additionally the FENa indicating that at least part of the overall reduction in Na+ reabsorption occurred in the proximal tubules. These results suggest antioxidant effects of MA can ameliorate oxidative stress and improve kidney function in diabetes mellitus.  相似文献   

18.
Kamiya H  Zhang W  Ekberg K  Wahren J  Sima AA 《Diabetes》2006,55(12):3581-3587
We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Wor rats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetes-induced reduction of unmyelinated fiber number (P < 0.01) and mean axonal size (P < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day.  相似文献   

19.
Small increases in blood pressure are a feature of incipient diabetic nephropathy, and mean blood pressure often correlates with the degree of albuminuria in such patients. Antihypertensive therapy with angiotensin converting enzyme inhibitors (CEI) or calcium channel blockers (CCB) has been assessed in several studies to determine if either form of treatment modifies incipient diabetic nephropathy and its evolution to established nephropathy. The acute renal hemodynamic effects of CEI differ from those of CCB under certain circumstances. In incipient diabetic nephropathy, therapy with CEI but not CCB tends to reduce filtration fraction, especially in hyperfiltering patients. In hypertensive patients with incipient diabetic nephropathy, both treatments result in a decrease in albuminuria and the responses are mainly dependent on the lowering of systemic blood pressure. In normotensive patients with incipient diabetic nephropathy, a lowering of mean blood pressure with CEI or CCB is not found consistently while effects on albuminuria are difficult to interpret. Short- and long-term therapy with CEI lowers or stabilizes albuminuria. Short-term administration of CCB has at times been associated with increases in albuminuria, but a comparison of CEI and CCB over 12 months in the Melbourne Diabetic Nephropathy Study (MDNS) has shown that both drugs stabilize albuminuria with no significant differences in their effects. Serial analysis of urinary sodium excretion in the MDNS shows that the hypotensive response to CEI in incipient nephropathy is highly dependent on sodium intake, and that sodium intake may modulate albuminuria during both CEI and CCB therapy.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

20.
Periodontal disease is a high prevalent disease.In the United States 47.2% of adults ≥ 30 years old have been diagnosed with some type of periodontitis.Longitudinal studies have demonstrated a two-way relationship between diabetes and periodontitis,with more severe periodontal tissue destruction in diabetic patients and poorer glycemic control in diabetic subjects with periodontal disease.Periodontal treatment can be successful in diabetic patients.Short term effects of periodontal treatment are similar in diabetic patients and healthy population but,more recurrence of periodontal disease can be expected in no well controlled diabetic individuals.However,effects of periodontitis and its treatment on diabetes metabolic control are not clearly defined and results of the studies remain controversial.  相似文献   

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