Risk Factors for Ocular Surface Irritation Symptoms in Inactive Mild and Moderate-to-Severe Graves' Orbitopathy.

INTRODUCTION: This study aims to analyze risk factors for ocular surface irritation symptoms in patients with non-corneal-damage inactive mild and moderate-to-severe Graves' orbitopathy (GO). METHODS: This retrospective study enrolled 307 patients with non-corneal-damage inactive GO admitted to Sun Yat-sen Memorial Hospital from April 2017 to September 2023. The activity and severity of GO were evaluated using the Clinical Activity Score (CAS) and the European Group on Graves' Orbitopathy (EUGOGO) classification, respectively. Multivariate logistic regression analysis was performed to analyze risk factors for ocular surface irritation symptoms. RESULTS: Among patients with inactive GO, for mild cases, CAS (P < 0.001), upper eyelid lag (P = 0.049), and extraocular muscle involvement (P = 0.019) in the symptomatic group were greater than those in the asymptomatic group, and multivariate logistic regression analysis demonstrated that upper eyelid lag (P = 0.048), CAS 1 (P < 0.001), CAS 2 (P = 0.005), and extraocular muscle involvement (P = 0.029) were risk factors for ocular surface irritation symptoms; for moderate-to-severe cases, CAS (P = 0.004), extraocular muscle involvement (P < 0.001), marginal reflex distance 1 (MRD1) (P = 0.030), and thyroid-stimulating hormone (TSH) (P = 0.034) in the symptomatic group were greater than those in the asymptomatic group, while multivariate logistic regression analysis indicated that extraocular muscle involvement (P = 0.018) and MRD1 (P = 0.012) were risk factors for ocular surface irritation symptoms. CONCLUSION: In non-corneal-damage inactive mild and moderate-to-severe GO, eyelid malposition and periocular muscle inflammation are risk factors for ocular surface irritation symptoms.

Graves' orbitopathy is the most common outward sign of Graves' disease. Patients with inactive Graves' orbitopathy often complain of ocular surface irritation symptoms. This study retrospectively collected clinical data from 307 patients with inactive Graves' orbitopathy and no concurrent corneal damage. The aim was to analyze risk factors for ocular surface irritation symptoms. Upper lid lag, eye movement disorder, and the Clinical Activity Score were found to be risk factors for mild cases. Eye movement disorder and the distance between the upper eyelid margin and corneal reflection point were risk factors for moderate-to-severe cases. To reduce symptoms, it may be helpful to treat inflammation around the eyes and address any eyelid abnormalities.

The Outcomes of Balanced Orbital Decompression for Dysthyroid Optic Neuropathy: Focusing on Choroiretinal Folds with and without Optic Disc Edema.

Purpose: To assess the outcomes of balanced orbital decompression for chorioretinal folds (CRFs) with and without optic disc edema (ODE) in dysthyroid optic neuropathy (DON). Method: A retrospective, interventional study was performed at Sun Yat-sen Memorial Hospital from April 2018 to November 2021. We collected the medical records of 13 patients (24 eyes) with DON and CRFs. Then, we divided them into the ODE group (15 eyes, 62.5%) and the non-ODE group (NODE group, 9 eyes, 37.5%). The valid ophthalmic examination parameters of 8 eyes in each group after balanced orbital decompression were compared at the 6-month follow-up. Results: The mean best corrected visual acuity (BCVA, 0.29 ± 0.27) and visual field-mean deviation (VF-MD, -6.55 ± 3.71 dB) in the ODE group were significantly worse than those in the NODE group (0.06 ± 0.15 and -3.49 ± 1.56 dB; all p < 0.01). Six months after orbital decompression, all parameters were found to have significantly improved in both groups, including BCVA and VF-MD (all p < 0.05). Moreover, the improvement amplitude of BCVA (p = 0.020) in the ODE group was significantly greater than that in the NODE group. There was no difference in BCVA between the ODE group (0.13 ± 0.19) and the NODE group (0.10 ± 0.13). The disc edema of all eyes (8/8 eyes, 100%) in the ODE group was completely mitigated after orbital decompression. The CRF resolution of 2 eyes (2/8 eyes, 25%) in the ODE group and no eyes in the NODE group was mitigated. Conclusions: Balanced orbital decompression can significantly improve visual functions and eliminate optic disc edema in DON patients, whether CRF relieves or not.

The Clinical Features of Graves' Orbitopathy with Elevated Intraocular Pressure.

BACKGROUND: To investigate the clinical characteristics of Graves' orbitopathy (GO) with elevated intraocular pressure (IOP) using the European Group of Graves' Orbitopathy (EUGOGO) system. METHODS: In this retrospective study, the clinical data of GO patients with elevated IOP (≥21 mmHg) were collected in Sun Yat-sen Memorial Hospital from January 2010 to June 2016. The demographic characteristics, clinical history of thyroid disease and GO, and ocular examination data were evaluated, and the activity and severity of GO were classified. RESULTS: Data were collected from 58 eyes of 39 patients. The durations of thyroid disease and GO were 15.9 ± 18.9 months and 7.5 ± 6.2 months, respectively. The average IOP was 24.8 ± 5.3 mmHg (range: 21-55 mmHg). No significant difference in IOP was observed between active and inactive eyes. Eight eyes (13.8%), 29 eyes (50.0%), and 21 eyes (36.2%) were graded as mild, moderate-severe, and sight-threatening disease, respectively, according to the EUGOGO classification. The IOP was not significantly different among the three EUGOGO grades. No glaucomatous optic nerve damage or visual field defects were found. CONCLUSION: Increased IOP was evident for every grade of GO severity and activity of the EUGOGO system. IOP, glaucomatous optic nerve damage, and visual fields must be evaluated regularly during follow-up evaluations, regardless of the degree of activity and severity of GO.

Evaluation of the Graves' Orbitopathy-Specific Quality of Life Questionnaire in the Mainland Chinese Population.

PURPOSE: To study the clinical significance of the Graves' orbitopathy-specific quality of life (GO-QOL) questionnaire in mainland Chinese patients. METHODS: A cross-sectional study was performed at the Ophthalmology Department of the Sun Yat-sen Memorial Hospital from April 2017 to April 2018. Eighty-eight consecutive Graves' orbitopathy (GO) patients completed the two subscales of the GO-QOL questionnaire: visual functioning and appearance. The disease severity of GO was measured by the European Group on Graves' Orbitopathy (EUGOGO) classification, and clinical activity was evaluated by the clinical activity score (CAS). RESULTS: The mean scores of GO-QOL questionnaire for the visual functioning and appearance subscales were 68.4 ± 31.2 and 62.0 ± 27.4, respectively. Lower QOL scores for the visual functioning subscale were significantly correlated with disease severity, the CAS and diplopia (all p < 0.05). Lower QOL scores for appearance were significantly correlated with the CAS (p < 0.05). Although no correlation was found between the appearance subscale scores and disease severity (p=0.407), a downward trend in the appearance subscale scores as the severity of GO increased from mild to sight-threatening GO was found. CONCLUSION: A strong correlation between disease severity and clinical activity has been shown in the GO-QOL questionnaire, suggested by the EUGOGO. The GO-QOL questionnaire is a simple and effective appraisal instrument in the evaluation of health-related QOL in the mainland Chinese patients with GO.

Effect of intensive insulin treatment on plasma levels of lipoprotein-associated phospholipase A2 and secretory phospholipase A2 in patients with newly diagnosed type 2 diabetes.

BACKGROUND: China has the highest absolute disease burden of diabetes worldwide. For diabetic patients, diabetes-related vascular complications are major causes of morbidity and mortality. The roles of lipoprotein-associated phospholipase A2 (Lp-PLA2) and secretory phospholipase A2 (sPLA2) as inflammatory markers have been recently evaluated in the pathogenesis of both diabetes and atherosclerosis. We aimed to determine the mechanism through which patients with newly diagnosed type 2 diabetes gain long-term vascular benefit from intensive insulin therapy by evaluating the change in Lp-PLA2 and sPLA2 levels after early intensive insulin treatment and its relevance with insulin resistance and pancreatic ß-cell function. METHODS: In total, 90 patients with newly diagnosed type 2 diabetes mellitus were enrolled. All patients received continuous subcutaneous insulin infusion (CSII) for approximately 2 weeks. Intravenous glucose-tolerance test (IVGTT) and oral glucose-tolerance test (OGTT) were performed, and plasma concentrations of Lp-PLA2 and sPLA2 were measured before and after CSII. RESULTS: Levels of Lp-PLA2 and sPLA2 were significantly higher in diabetic patients with macroangiopathy than in those without (P < 0.05). After CSII, the sPLA2 level decreased significantly in all diabetic patients (P < 0.05), while the Lp-PLA2 level changed only in those with macroangiopathy (P < 0.05). The area under the curve of insulin in IVGTT and OGTT, the acute insulin response (AIR3-5), early phase of insulin secretion (ΔIns30/ΔG30), modified ß-cell function index, and homeostatic model assessment for ß-cell function (HOMA-ß) increased after treatment even when adjusted for the influence of insulin resistance (IR; P < 0.001). The HOMA-IR was lower after treatment, and the three other indicators adopted to estimate insulin sensitivity (ISIced, IAI, and QUICKI) were higher after treatment (P < 0.05). Correlation analysis showed that the decrease in the Lp-PLA2 and sPLA2 levels was positively correlated with a reduction in HOMA-IR after CSII (P < 0.05). Additionally, multiple linear regression analysis showed that Lp-PLA2 and sPLA2 independently correlated with HOMA-IR (P < 0.05). CONCLUSIONS: Lp-PLA2 and sPLA2 are closely related to insulin resistance and macroangiopathy in diabetic patients. Intensive insulin therapy might help improve IR and protect against diabetic macroangiopathy by influencing the Lp-PLA2 and sPLA2 levels. TRIAL REGISTRATION: ChiCTR-TRC-10001618 2010 September 16.

Prevalence of dyslipidemia and its control in type 2 diabetes: A multicenter study in endocrinology clinics of China.

OBJECTIVE: The aim of this study was to assess the levels of serum lipid and awareness, treatment, and control of dyslipidemia in type 2 diabetes mellitus (T2DM) patients from top-ranked endocrinology clinics in large cities of China. MATERIALS AND METHODS: A cross-sectional study in a representative sample of 4807 Chinese adults 40 to 75 years of age was conducted during 2010 to 2011 at 20 endocrinology clinics in top-ranked hospitals covering most of the major cities of China. Serum lipid levels were measured, and treatment of dyslipidemia was recorded and assessed. RESULTS: In the present study, the prevalence of dyslipidemia was 67.1% in T2DM subjects. Among those with dyslipidemia, the proportion of awareness and treatment was 68.7% and 55.9%. Among participants with lipid-lowering therapy, 686 subjects achieved the low-density lipoprotein cholesterol (LDL-C) control less than 2.60 mmol/L, with the rate being 39.4%. In those patients with previous cardiovascular disease, the percentage of participants who achieved LDL-C goal (1.80 mmol/L) was 15.3%. CONCLUSION: The prevalence of dyslipidemia is high, and the awareness, treatment, and control of dyslipidemia are relatively low in Chinese T2DM patients. This calls for the awareness and intervention of dyslipidemia in these patients.

Predictive factors of thyroid cancer in patients with Graves' disease.

BACKGROUND: The best preoperative examination in Graves' disease with thyroid cancer still remains uncertain. The objectives of the present study were to investigate the prevalence of thyroid cancer in Graves' disease patients, and to identify the predictive factors and ultrasonographic features of thyroid cancer that may aid the preoperative diagnosis in Graves' disease. METHODS: This retrospective study included 423 patients with Graves' disease who underwent surgical treatment from 2002 to 2012 at our institution. The clinical features and ultrasonographic findings of thyroid nodules were recorded. The diagnosis of thyroid cancer was determined according to the pathological results. RESULTS: Thyroid cancer was discovered in 58 of the 423 (13.7 %) surgically treated Graves' disease patients; 46 of those 58 patients had thyroid nodules, and the other 12 patients were diagnosed with incidentally discovered thyroid carcinomas without thyroid nodules. Among the 58 patients with thyroid cancer, papillary microcarcinomas were discovered in 50 patients, and multifocality and lymph node involvement were detected in the other 8 patients. Multivariate regression analysis showed younger age was the only significant factor predictive of metastatic thyroid cancer. Ultrasonographic findings of calcification and intranodular blood flow in thyroid nodules indicate that they are more likely to harbor thyroid cancers. CONCLUSIONS: Because the influencing factor of metastatic thyroid cancers in Graves' disease is young age, every suspicious nodule in Graves' disease patients should be evaluated and treated carefully, especially in younger patients because of the potential for metastasis.

[A Meta-analysis on the association between adiponectin gene 45T/G/276G/T polymorphisms and type 2 diabetes in Chinese population].

OBJECTIVE: Association between the 45T/G and 276G/T single nucleotide polymorphisms of adiponectin gene and the occurrence of type 2 diabetes in Chinese population was studied. METHODS: 20 studies consisting 22 case-control comparisons about 45T/G polymorphism and nine case-control studies about 276G/T polymorphism that were based on our inclusion criterion and available in the literature were reviewed. RESULTS: Results from Meta-analysis demonstrated a large heterogeneity among the studies both on 45T/G and 276G/T polymorphisms and a significant association was observed between 45T/G polymorphism at exon 2 of the adiponectin gene and type 2 diabetes among the Chinese population.45G allele appeared to be one of the genetic risk factors for susceptibility to type 2 diabetes with a random effects odds ratio (OR) of 1.43 (95%CI: 1.17 - 1.75), and the G allele carriers were more susceptible to the disease with an OR of 1.38 (95%CI: 1.04 - 1.84). Results from Meta-analysis, however, showed no association between the 276G/T polymorphism and type 2 diabetes in the Chinese population, while the random effects OR of the allele 276T to susceptibility of disease was 0.83 (95%CI: 0.61 - 1.13). CONCLUSION: The current paper on Meta-analysis demonstrated a correlation between the 45T/G single nucleotide polymorphism and the occurrence of type 2 diabetes in Chinese population, which was different from the findings that such an association with 276G/T polymorphism could not be demonstrated in the same ethnic population.

Association between peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C.

BACKGROUND: Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1alpha and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1alpha gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C. METHODS: The SNPs in all exons of the PGC-1alpha gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1alpha gene alter the interaction with MEF2C. RESULTS: Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1alpha gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P < 0.01). Even in controls, the 482Ser (A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly (G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between 482Ser variant and MEF2C. CONCLUSIONS: The results suggested that the 482Ser variant of PGC-1alpha conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants (Gly482Ser, Thr394Thr) in the PGC-1alpha gene and MEF2C.

Effect of angiotensin II receptor blocker on glucose-induced mRNA expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in rat mesangial cells.

BACKGROUND: The decreased degradation of extra-cellular matrix proteins plays an important role in the onset of diabetic nephropathy. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1), which are members of the matrix metalloproteinase family, are associated with this process. Angiotensin II (AII) plays an important role in the development of diabetic nephropathy also. This research aimed to investigate the effect of angiotensin II receptor blocker on glucose-induced mRNA expressions of MMP-9 and TIMP-1 in rat mesangial cells. METHODS: Rat mesangial cells were cultured and divided into 5 groups: normal glucose (group NG), high glucose (group HG), group NG + AII, NG + AII + saralasin (group NG + AII + S, saralasin is the AII receptor blocker) and HG + saralasin (group HG + S). After the cells were incubated for 24 hours, AII concentrations in the supernatant were measured by radioimmunoassay and the expression of MMP-9 and TIMP-1 mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: AII concentrations were higher in group HG ((56.90 +/- 13.54) pg/ml) and group HG + S ((51.30 +/- 5.96) pg/ml) than in group NG ((37.89 +/- 8.62) pg/ml, P < 0.05), whereas there was no significant difference between group HG and group HG + S. The expression of MMP-9 mRNA and MMP-9/TIMP-1 mRNA ratio in group NG + AII (MMP-9, 0.33 +/- 0.04; MMP-9/TIMP-1, 0.40 +/- 0.06) and group HG (MMP-9, 0.36 +/- 0.02; MMP-9/TIMP-1, 0.45 +/- 0.03) were decreased more significantly than those in group NG (MMP-9, 0.72 +/- 0.02; MMP-9/TIMP-1, 1.21 +/- 0.07). These values in group NG + AII + S (MMP-9, 0.71 +/- 0.02; MMP-9/TIMP-1, 1.18 +/- 0.05) were higher than those in group NG + AII, and the values in group HG + S (MMP-9, 0.71 +/- 0.02; MMP-9/TIMP-1, 1.16 +/- 0.05) were higher than those in group HG (all were P < 0.05). TIMP-1 mRNA expression was increased more significantly in group NG + AII (0.81 +/- 0.03) and group HG (0.80 +/- 0.03) than in group NG (0.59 +/- 0.02), but it was lower in group NG + AII + S (0.60 +/- 0.01) than in group NG + AII and also lower in group HG + S (0.61 +/- 0.01) than in group HG (all were P < 0.05). CONCLUSIONS: High glucose stimulates AII production. Both high glucose and AII induce a decrease in MMP-9 mRNA expression and MMP-9/TIMP-1 mRNA ratio as well as an increase in TIMP-1 mRNA expression, which can be reversed by saralasin, suggesting that high glucose can aggravate impaired matrix degradation by altering gene expression of MMP-9 and TIMP-1 and that the effect of high glucose may be mediated by AII.

A meta-analysis of relationship between beta-fibrinogen gene -148C/T polymorphism and susceptibility to cerebral infarction in Han Chinese.

OBJECTIVE: The results of studies on association between -148C/T polymorphism in promoter region of beta-fibrinogen gene and susceptibility to cerebral infarction in Chinese population are controversial. In this study, we summarize the results of published works in this field by a meta-analysis. Data sources Genetic association studies evaluating the beta-fibrinogen gene -148C/T polymorphisms and cerebral infarction involving Chinese population published before December 2005 were collected from PubMed, EMBASE and CNKI. Study selection Case control studies involving unrelated, Han subjects aged from 18 to 80 years, and the internationally recognized diagnostic standard of cerebral infarction and genotype frequencies in control group consistent with Hardy-Weinberg equilibrium were used. Publication bias was tested by funnel plot and the odds ratios of all studies were combined dependent on the result of heterogeneity test among the individual studies. The software Review Manager (Version 4.2) was used for meta-analysis. RESULTS: Eleven studies including 1223 patients and 1433 controls met the selection criteria. There was no heterogeneity among the odds ratios (ORs) of individual studies (chi(2) = 17.82, P = 0.06). The combined OR of susceptibility to cerebral infarction in -148T allele carriers compared to the wild homozygote was 1.32 (95% CI 1.12 to 1.55, P = 0.0008). In the patients with cerebral infarction, the average plasma fibrinogen level of allele T carrier was 0.42 g/L (95% CI 0.29 to 0.54, P < 0.001), higher than that of -148C/C homozygous ones. CONCLUSIONS: beta-fibrinogen gene -148C/T polymorphism might contribute to susceptibility to cerebral infarction in Han Chinese. To reach a definitive conclusion, further gene to gene and gene to environment interactions studies on beta-fibrinogen polymorphisms and cerebral infarction with large sample size are required.

A meta-analysis of beta-fibrinogen gene-455G/A polymorphism and plasma fibrinogen level in Chinese cerebral infarction patients.

OBJECTIVE: To evaluate the correlation between the beta-fibrinogen gene-455G/A polymorphism and cerebral infarction in Chinese population by means of meta-analysis. METHODS: Genetic association studies on evaluating the beta-fibrinogen gene -455G/A polymorphism and cerebral infarction involving Chinese population published before December 2005 were collected from database of PubMed, EMBASE, and CNKI. All the data in literature were abstracted based on the defined selection criteria by two independent investigators. Publication bias was tested by funnel plot and the odd ratios of all studies were combined dependent on the result of heterogeneity test among the individual studies. The software Review Manager (Version 4.2) was used for meta-analysis. RESULTS: Eleven studies including 1405 patients and 1600 controls met the selection criteria. There was no publication bias in 11 reviewed studies. Heterogeneity test of reviewed studies showed statistically significant differences (chi2=24.58, P=0.006) among the ORs of individual studies. The combined OR of 11 studies of susceptibility to cerebral infarction in -455A allele carriers compared with the -455G/G wild homozygotes was 1.33 (95%CI 1.04-1.71, P=0.02). In the patients with cerebral infarction in 6 studies, the summarized average plasma fibrinogen level of allele A carrier was 0.29 g/L (95%CI 0.14-0.44, P=0.0002) higher than that of -455G/G homozygous ones. CONCLUSIONS: beta-fibrinogen gene -455G/A polymorphism might contribute to susceptibility of cerebral infarction in Chinese population; allele A increases the individual susceptibility to the disease.

Effect of losartan on the mRNA expressions of MT3-MMP and TIMP-2 in diabetic kidneys.

BACKGROUND AND OBJECTIVES: The renin-angiotensin system plays a critical role in circulatory homoeostasis. Evidence has emerged that suggests a pathologic role for angiotensin II in patients with kidney disease. Losartan is an antagonist of angiotensin II and blocks the angiotensin II type-1 receptor. Thus it may reduce proteinuria and delay the progression of renal disease in diabetic nephropathy. We investigated the effects of losartan on the mRNA expressions of membrane-type3 matrix metalloproteinases (MT3-MMP) and the tissue inhibitor of metalloproteinase-2 (TIMP-2) in diabetic kidneys in order to evaluate degradation and remodeling of the extracellular matrix. METHODS: Male Wistar rats were divided into 3 groups. Group A was the control group containing healthy rats (n = 11), group B comprised diabetic rats without any therapy (n = 11), and group C consisted of diabetic rats treated with losartan (n = 9). 24-hr urine samples were collected in order to measure urinary albumin excretion (UAE). After a period of 18 weeks, the kidneys were extracted from all rats in order to measure the mRNA expressions of MT3-MMP, TIMP-2 and transforming growth factor-beta1 (TGF-beta1) by RT-PCR. We also examined the glomerular basement membrane thickening and the mesangial matrix (MM) density (MM area/mesangial area). RESULTS: The expression of renal MT3-MMP mRNA in group B (1.37 +/- 0.96) was significantly higher than that in group A (0.75 +/- 0.34, p < 0.05), but also significantly higher than in group C (0.75 +/- 0.30, p < 0.05). Similarly, the mRNA expression of renal TIMP-2 in group B (0.73 +/- 0.37) was significantly increased compared to that in group A (0.32 +/- 0.19, p < 0.05), but also higher than in group C (0.34 +/- 0.17, p < 0.05). In addition, subjects in group B showed abundant TGF-beta1 mRNA expression and UAE compared to groups A and C, as well as significantly higher glomerular basement membrane thickening and MM density (all p < 0.05). CONCLUSIONS: We conclude that MT3-MMP and TIMP-2 production in the renal cortex of diabetic kidneys is increased. Losartan can prevent the development of diabetic nephropathy by decreasing MT3-MMP and TIMP2 production in diabetic kidneys.