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The kidney is one of the major organs involved in whole-body homeostasis while chronic renal impairment usually leads to fat redistribution and hyperlipidemia. The aim of this study was to elucidate the role of tissue renal renin-angiotensin system (RAS) components, lipogenic peroxisome proliferator-activated receptor-gamma (PPARgamma), and cytokine TNF-alpha in the development of ectopic adipogenesis and lipid deposition. Adult male Sprague-Dawley rats were randomized into three groups: untreated uninephrectomized (UNX) rats, UNX rats treated with an angiotensin-converting enzyme inhibitor (ACEI), lisinopril, and sham-operated rats. All animals were euthanized at 10 mo postoperation. The untreated UNX rats showed increased protein expression of renin, angiotensinogen, PPARgamma, and the angiotensin II type 2 receptor (AT2R) but reduced protein expression of AT1R and TNF-alpha in their remnant kidneys. Immunofluorescence staining revealed increased reactivity of angiotensinogen and angiotensin I/II in renal tubular cells and adipocytes of the untreated UNX rats. ACEI treatment largely prevented these disorders in association with restored normolipidemia and normalized renal adipogenesis and lipid deposition. These findings support the notion that tissue RAS, PPARgamma, and TNF-alpha collectively play an important role in the renal adipogenesis and lipid metabolism.

Nephrectomized rats have widely been used to study chronic renal failure. Interestingly, renal cell carcinoma occurred in the remnant kidney after uninephrectomy (UNX). In this study, we probed insulin-like growth factor (IGF)-1 signaling pathway in UNX-induced renal cancer. Adult male Sprague-Dawley rats were randomized into two groups: UNX rats (n = 22) and sham-operated rats (n = 12). Rats were killed at 3, 7, and 10 months. After 7 months after nephrectomy, the UNX rats developed renal cell carcinoma with increased expression of proliferating cell nuclear antigen, and 68.2% (15/22) of the animals exhibited invasive carcinoma. Western blot demonstrated significant down-regulation of IGF binding protein 3 contrasting with the up-regulation of protein kinase Czeta and Akt/protein kinase B in the renal cancer tissues. These findings indicate a unique rat model of UNX-induced renal cancer associated with enhanced IGF-1 signaling pathway.

It is widely accepted that human islet amyloid polypeptide (hIAPP) aggregation plays an important role in the loss of insulin-producing pancreatic beta cells. hIAPP-induced cytotoxicity is mediated by generation of reactive oxygen species (ROS). Phycocyanin (PC) is a natural compound from blue-green algae that is widely used as food supplement. Currently, little is known about the effects of PC on beta cells with the presence of hIAPP. The aim of this study was to investigate the in vitro protective effects of PC on INS-1E rat insulinoma beta cells against hIAPP-induced cell death, as well as the underlying mechanisms. Our results showed that hIAPP-induced cell death with apoptotic characteristics including growth inhibition, chromatin condensation and DNA fragmentation. However, cytotoxicity of hIAPP was significantly attenuated by co-incubation of the cells with PC. The results of Western blotting showed that activation of caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP) in hIAPP-treated cells was blocked by PC. Moreover, PC significantly prevented the hIAPP-induced overproduction of intracellular ROS and malondialdehyde (MDA), as well as changes in activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) enzymes. Furthermore, hIAPP triggered the activation of mitogen-activated protein kinases (MAPKs), and these effects were effectively suppressed by PC. Taken together, our results suggest that PC protects INS-1E pancreatic beta cells against hIAPP-induced apoptotic cell death through attenuating oxidative stress and modulating c-Jun N-terminal kinase (JNK) and p38 pathways.

The amyloid hypothesis of type 2 diabetes mellitus postulates that elevated levels of normally expressed monomeric proteins of human islet amyloid polypeptide (hIAPP) trigger oligomerization that independently causes fibril formation and disease progression. The aim of this study was to demonstrate the existence of amyloid oligomers in human pancreatic islets. Human pancreas tissues were obtained at autopsy of 8 nondiabetic control subjects (mean age = 75.8 +/- 11.7 years, 4 males), 8 type 2 diabetic cases without islet amyloid (mean age = 78.8 +/- 8.5 years, 4 males), and 8 type 2 diabetic patients with islet amyloid (mean age = 73.7 +/- 14.2 years, 4 males). Several markers for insulin, IAPP, amyloid fibrils (thioflavin T), and apoptosis (cleaved caspase-3) were used in combination with an oligomer-specific antibody. Two distinct forms of oligomers were found in pancreatic islets. Small spherical puncta were found in approximately 3% to 20% of the islet cells of nondiabetic subjects, and large curvilinear structures as extracellular oligomers were identified frequently in diabetic islets. Large oligomers were spatially localized adjacent to amyloid fibrils and were associated with apoptosis. This report demonstrates the presence of 2 morphologic classes of amyloid oligomers in human pancreatic islets. The observations warrant function studies to investigate the clinical implications of the amyloid oligomerization in the pathogenesis of type 2 diabetes.

Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.

Background and Purpose: Magnetic resonance imaging (MRI) has been widely applied in detecting intracranial large artery stenosis, but there have been few validation studies to compare with histopathology. The aim of the postmortem study is to assess the accuracy of MRI in identifying middle cerebral artery (MCA) stenosis., Methods: We recruited, consecutively, Chinese postmortem autopsies in our hospital during 19 months. MRI was performed in the postmortem brains to scan the cross-sections of MCAs with barium expanding the artery lumen. The MCAs were then removed for histopathologic studies. With histopathology as a reference standard, the accuracy of MRI was evaluated, and the correlation between MCA stenosis identified by MRI and radiologically or histopathologically evident brain infarcts was investigated., Results: Seventy-six consecutive autopsies were recruited. The sensitivity and specificity of MRI in detecting more than 30% MCA stenosis were 38.6% and 92.2%, with a positive predictive value of 87.2% and negative predictive value of 52.2%, and the corresponding values of MRI in identifying more than 50% MCA stenosis were 57.1%, 90.8%, 50%, and 83.0%, respectively. Both more than 30% and more than 50% MCA stenosis identified by MRI were found to be associated with infarctions in the corresponding MCA territory (P= 0.001, odds ratio = 4.365, 95% CI: 1.684-11.313; and P= 0.039, odds ratio = 2.694, 95% CI: 1.139-6.377)., Conclusions: Our study demonstrates the agreement between ex vivo MRI and histopathology in identifying MCA stenosis, and the correlation between the MCA stenosis identified by MRI and radiologically or histopathologically evident brain infarcts.

This review focuses on the efficacy and safety of Chinese medicine in the treatment of type-2 diabetes. Included were 84 controlled clinical studies of type-2 diabetes treated with Chinese medicine for at least 1 month. Reported outcomes were: symptom relief; improvement in glycemia, insulin resistance and secondary failure, and adverse events. Symptom relief was achieved in most (>80%) of the patients receiving Chinese medicine. Compared with orthodox drugs, Chinese medicine had a 1.2-fold (95% CI 1.2-1.3) increase in symptom relief. The relative risk of achieving a fasting blood glucose of <7.3 mmol/l or a postprandial blood glucose of <8.2 mmol/l was: 3.0 (95% CI 1.4-6.5) for Chinese medicine plus diet versus diet; 2.0 (95% CI 1.4-3.0) for Chinese medicine versus placebo; 1.8 (95% CI 1.4-2.3) for combined Chinese medicine and orthodox drugs versus Yuquan Wan (a classic Chinese herbal formula for diabetes), 1.5 (95% CI 1.4-1.7) for combined Chinese medicine and orthodox drugs vs. orthodox drugs, and 1.3 (95% CI 1.2-1.5) for Chinese medicine versus orthodox drugs. A fasting blood glucose of <8.2 mmol/l plus symptom relief was observed in 71-100% of the patients with secondary failure to oral anti-diabetic drugs. Serious adverse events including hypoglycemic coma and death were caused by adulteration with orthodox drugs, erroneous substitution, self-meditation, overdoses, and improper preparation. Chinese herbal medicine should be used cautiously with doctors' prescription and follow-up. Long-term clinical studies may disclose the effectiveness of Chinese medicine in reducing the mortality and morbidity of diabetic complications.

Background: To provide an update on the latest evidence-based management of nephropathy in type 2 diabetes., Methods: A literature search (MEDLINE 1966 to 2002) was performed using the key words "diabetic nephropathy," and relevant book chapters were also reviewed, to identify well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy (DN). Data and conclusions from the selected articles that provided solid evidence regarding the optimal management of DN were extracted and interpreted in light of clinical and research experience with Chinese patients., Results: DN is the leading cause of end-stage renal disease worldwide. High blood pressure, dyslipidemia, long duration of diabetes, poor glycemic control and central obesity are important risk factors. Microalbuminuria is a practical marker to predict the development of overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycemic control is a fundamental goal, but effective antihypertensive and possibly lipid-lowering therapy delay the progression of DN. Recent large clinical trials support the earlier experimental data that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have important renoprotective actions independent of their blood pressure lowering actions., Conclusions: Screening for microalbuminuria and monitoring renal function will identify patients with DN at an early stage and allow for intervention. Tight glycemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.

Objective: To investigate the relative effects of degree and distribution of body fat with several cardiovascular disease (CVD) risk factors in elderly Chinese subjects., Methods: One hundred and thirty-five elderly Chinese individuals (age range, 60-65 y) without any history of significant renal, hepatic or cardiac disease were recruited. Seated blood pressure, anthropometric and fasting plasma biochemical parameters were measured. Student's t-test was used to compare the differences in biochemical and anthropometric markers between cohorts., Results: Males were heavier (64.6 +/- 8.6, 57.2 +/- 8.2kg, P < 0.001), taller (1.65 +/- 0.06, 1.51 +/- 0.05 m, P < 0.001) and their greater body fat was predominantly deposited centrally (Waist-to- hip ratio, 0.91 +/- 0.06, 0.88 +/- 0.07, P < 0.05). Females were more generally obese with increased body mass index (BMI, 23.8 +/- 4.6, 25.0 +/- 3.5 kg/m2, P < 0.05) and percentage body fat [26.3% (24.5%-28.1%) vs 37.2% (36.0%-38.9%), P < 0.001] than the males. However, despite an 11% higher proportion of body fat in females, no significant differences were identified in blood pressure, lipid profile, indices of insulin resistance or albumin-to-creatinine ratios., Conclusion: It is likely that central adiposity contributes disproportionately to these metabolic disorders in males even though they are much leaner than elderly Chinese females.

Purpose: To review evidence-based management of nephropathy in patients with type 2 diabetes., Data Sources: A literature search (MEDLINE 1966 to 2000) was performed using the key word "diabetic nephropathy". Relevant book chapters were also reviewed., Study Selection: Well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy were selected., Data Extraction: Data and conclusions from the selected articles that provide solid evidence to the optimal management of diabetic nephropathy were extracted and interpreted in light of our clinical research experience with many thousands of Hong Kong Chinese patients., Results: Hypertension, long diabetes duration, poor glycaemic control and central obesity are the most important risk factors. Microalbuminuria is a practical marker to predict overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycaemic control is the mainstay of treatment but effective antihypertensive therapy is also key to delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists have important renoprotective actions independent of their blood pressure lowering actions., Conclusions: Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Monitoring renal function and screening for microalbuminuria will allow the identification of patients with nephropathy at a very early stage for intervention. Tight glycaemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.