Diabetic complications are the major cause of morbidity and mortality in persons with diabetes. Chronic hyperglycemia is a major initiator of diabetic microvascular complications (eg, retinopathy, neuropathy, nephropathy). Glucose processing uses a variety of diverse metabolic pathways; hence, chronic hyperglycemia can induce multiple cellular changes leading to complications. Several predominant well-researched theories have been proposed to explain how hyperglycemia can produce the neural and vascular derangements that are hallmarks of diabetes. These theories can be separated into those that emphasize the toxic effects of hyperglycemia and its pathophysiological derivatives (such as oxidants, hyperosmolarity, or glycation products) on tissues directly and those that ascribe pathophysiological importance to a sustained alteration in cell signaling pathways (such as changes in phospholipids or kinases) induced by the products of glucose metabolism. This article summarizes these theories and the potential therapeutic interventions that may prevent diabetic complications in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.

Molecular Understanding of Hyperglycemia's Adverse Effects for Diabetic Complications

Emerging evidence suggests that transforming growth factor-β (TGF-β) is an important mediator of diabetic nephropathy. We showed previously that short-term treatment with a neutralizing monoclonal anti-TGF-β antibody (αT) in streptozotocin-diabetic mice prevents early changes of renal hypertrophy and increased matrix mRNA. To establish that overactivity of the renal TGF-β system mediates the functional and structural changes of the more advanced stages of nephropathy, we tested whether chronic administration of αT prevents renal insufficiency and glomerulosclerosis in the db/db mouse, a model of type 2 diabetes that develops overt nephropathy. Diabetic db/db mice and nondiabetic db/m littermates were treated intraperitoneally with αT or control IgG, 300 μg three times per week for 8 wk. Treatment with αT, but not with IgG, significantly decreased the plasma TGF-β1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency, and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding α1(IV) collagen and fibronectin. On the other hand, treatment with αT completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine clearance, and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantly affected by αT treatment. We conclude that chronic inhibition of the biologic actions of TGF-β with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

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Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice

Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics.

Given their essential function in aerobic metabolism, mitochondria are intuitively of interest in regard to the pathophysiology of diabetes. Qualitative, quantitative, and functional perturbations in mitochondria have been identified and affect the cause and complications of diabetes. Moreover, as a consequence of fuel oxidation, mitochondria generate considerable reactive oxygen species (ROS). Evidence is accumulating that these radicals per se are important in the pathophysiology of diabetes and its complications. In this review, we first present basic concepts underlying mitochondrial physiology. We then address mitochondrial function and ROS as related to diabetes. We consider different forms of diabetes and address both insulin secretion and insulin sensitivity. We also address the role of mitochondrial uncoupling and coenzyme Q. Finally, we address the potential for targeting mitochondria in the therapy of diabetes. Antioxid. Redox Signal. 12, 537–577.

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Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities

Diabetic nephropathy is characterized by excessive deposition of extracellular matrix proteins in the mesangium and basement membrane of the glomerulus and in the renal tubulointerstitium. This review summarizes the main changes in protein composition of the glomerular mesangium and basement membrane and the evidence that, in the mesangium, these are initiated by changes in glucose metabolism and the formation of advanced glycation end products. Both processes generate reactive oxygen species (ROS). The review includes discussion of how ROS may activate intracellular signaling pathways leading to the activation of redox-sensitive transcription factors. This in turn leads to change in the expression of genes encoding extracellular matrix proteins and the protease systems responsible for their turnover.

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Extracellular Matrix Metabolism in Diabetic Nephropathy

http://www.prp.net.br/adm/pdf/TGF%20diabeticos.PDF

Quantification of glomerular TGF-β1 mRNA in patients with diabetes mellitus

Background: Oxidative stress is an important pathogenetic factor in underlying diabetic complications. Recently, 8-hydroxy-2′-deoxyguanosine (8-OHdG) has been reported to serve as a

Oxidative DNA Damage and Tubulointerstitial Injury in Diabetic Nephropathy

Work-related Aggression and Violence Committed by Patients and Its Psychological Influence on Doctors: Keigo S aeki , et al. Department of Community Health and Epidemiology, Nara Medical University School of Medicine—Objectives: To determine the incidence rate of work-related aggression and violence (WRAV) against doctors and investigate risk factors and psychological influences of WRAV doctors. Methods: We sent a self-administered questionnaire on WRAV committed by patients and their associates to 1,148 doctors in Nara Prefecture, Japan. We calculated the incidence rate of WRAV using the number of incidents encountered during the previous 12 mo and the doctor's average weekly working hours. Risk factors for the incidence WRAV were analyzed by Poisson regression, and the influence of WRAV on the symptoms of post-traumatic stress disorder (PTSD) was evaluated by multiple logistic regression analysis. Results: A total of 758 (66.0%) doctors returned the questionnaire. The incidence rate of WRAV was 0.20 (95% CI: 0.17-0.24)×10 -3 per practice hour. Adjusted incidence rate ratios of WRAV were significantly increased among doctors 1) with a shorter career (11.0; 95% CI: 5.0-24.2), 2) working in a region with the lowest average taxable income (1.6; 1.1-2.4), and 3) whose specialties were dermatology (3.8; 2.3-6.3), psychiatry (2.7; 1.3-5.6) and ophthalmology (1.9; 1.2-3.2). Of 289 subjects who had encountered WRAV at least once during their career, 26 doctors (8.2%) had symptoms suggestive of PTSD due to the most severe incident. Conclusions: Doctors encountered WRAV at an incidence rate of 0.20×10 -3 per practice hour, and some of them might develop PTSD. Countermeasures are required to maintain sound health and safe workplaces for doctors. (J Occup Health 2011; 53: 356-364)

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Work-related aggression and violence committed by patients and its psychological influence on doctors.

We evaluated the diagnostic utility of urinary transferrin (Tf) in patients with diabetic nephropathy by comparing the diagnostic findings with those of clinical stage and renal biopsy specimens. According to the rate of urinary albumin excretion, a total of 60 patients with non-insulin-dependent diabetes mellitus were separated into normoalbuminuria ( 288 mg/day). They were also divided into 5 groups, D0, DI, DII, DIII and DIV according to the severity of glomerular diffuse lesions using Gellman's criteria. Thirty-eight non-diabetic volunteers were used as controls. Using 24-hour urine specimens, Tf was measured by latex-immuno-turbidimetry. Urinary concentrations of albumin, alpha 1-microglobulin, beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) were also evaluated. Urinary Tf was significantly increased in the diabetic patients relative to the non-diabetic controls. The incidence of microtransferrinuria (440 approximately 4,400 micrograms/day) was 33.3% in normoalbuminuria, 63.2% in microalbuminuria, and 18.2% in overt proteinuria. The incidence of overt transferrinuria (> 4,400 micrograms/day) was 0%, 36.8% and 81.8%, respectively. Among the diabetic patients, urinary Tf showed a significant increase with respect to the progress of glomerular diffuse lesions. The glomerular diffuse lesions of 10 normoalbuminuric cases with microtransferrinuria were graded as DI in 8 cases, DII in 1 case, and DIII in 1 case. There was a significant correlation between the urinary excretion of Tf and that of albumin, alpha 1-microglobulin or NAG. The findings indicate that urinary Tf may be useful in detecting diabetic nephropathy at an early stage.

Diagnostic significance of urinary transferrin in diabetic nephropathy

We evaluated the role of tissue inhibitors of metalloproteinase-1 (TIMP-1) in patients with diabetic nephropathy by comparing the serum and urine TIMP-1 levels with those of renal biopsy specimens. A total of 35 diabetic patients were divided into four groups, D0, DI, DII and DIII-IV, according to the severity of diffuse glomerular lesions using Gellman's criteria. Using serum and 24-hour urine specimens, TIMP-1 was measured by a sandwich enzyme immunoassay. Serum and urinary TIMP-1 showed significant increases in association with the progress of glomerular diffuse lesions. There was no correlation between serum TIMP-1 and serum creatinine, creatinine clearance, serum and urinary beta 2-microglobulin, urinary NAG, HbA1c, or urinary TIMP-1. There was a significant correlation between urinary TIMP-1 and urinary albumin, and was a significant correlation between urinary TIMP-1 and urinary NAG. We conclude that TIMP-1 has a potential role in the regulation of glomerular matrix accumulation in diabetic nephropathy.

Hisayuki Nishioka

Papers

Quantification of glomerular TGF-β1 mRNA in patients with diabetes mellitus

Oxidative DNA Damage and Tubulointerstitial Injury in Diabetic Nephropathy

Work-related aggression and violence committed by patients and its psychological influence on doctors.

Diagnostic significance of urinary transferrin in diabetic nephropathy

Role of tissue inhibitors of metalloproteinase in diabetic nephropathy