Hai-Lu Zhao

Associations of Hyperglycemia and Insulin Usage With the Risk of Cancer in Type 2 Diabetes: The Hong Kong Diabetes Registry

OBJECTIVE Insulin has mitogenic effects, although hyperglycemia may be a risk factor for cancer in type 2 diabetes. It remains uncertain whether use of insulin increases cancer risk because of its effect on cell growth and proliferation or decreases cancer risk because of its glucose-lowering effect. RESEARCH DESIGN AND METHODS A 1:2-matched new insulin user cohort on age (±3 years), smoking status, and likelihood of initiating insulin therapy (±0.05) was selected from a cohort of 4,623 Chinese patients with type 2 diabetes, free of cancer, and naive to insulin at enrollment. Stratified Cox regression analysis on the matched pairs was used to obtain hazard ratios (HRs) of insulin therapy and A1C for cancer risk. A structured adjustment scheme was used to adjust for covariates. RESULTS Of 973 new insulin users, 971 had matched nonusers (n = 1935). The cancer incidence in insulin nonusers was much higher than that in insulin users (49.2 vs. 10.2, per 1,000 person-years, P < 0.0001). After further adjustment for all other covariates with a P value less than 0.3 and nonlinear associations with cancer, A1C was associated with an increased cancer risk (HR per percentage 1.26, 95% CI 1.03–1.55), whereas use of insulin was associated with a decreased cancer risk (HR of insulin users vs. nonusers: 0.17, 0.09–0.32). Consistent results were found in analyses including all 973 insulin users and 3,650 nonusers. CONCLUSIONS In Chinese patients with type 2 diabetes, hyperglycemia predicts cancer, whereas insulin usage was associated with a reduced cancer risk.

A systematic review on use of Chinese medicine and acupuncture for treatment of obesity

Obesity is a major health hazard and despite lifestyle modification, many patients frequently regain any lost body weight. The use of western anti‐obesity drugs has been limited by side effects including mood changes, suicidal thoughts, and gastrointestinal or cardiovascular complications. The effectiveness and safety of traditional Chinese medicine including Chinese herbal medicine (CHM) and acupuncture provide an alternative established therapy for this medical challenge. In this systematic review, we used standard methodologies to search, review, analyse and synthesize published data on the efficacy, safety and relapse of weight regain associated with use of CHM and acupuncture. We also examined the rationale, mechanisms and potential utility of these therapies. A total of 12 electronic databases, including Chinese, English, Korean and Japanese, were searched up to 28 February 2010. Randomized controlled trials (RCTs) for CHM and/or acupuncture with comparative controls were considered. We used the Jadad scale to assess methodological qualities, the random effect model in the pooled analysis of therapeutic efficacy to adjust for heterogeneity and funnel plots to explore publication bias. After screening 2,545 potential articles from the electronic databases, we identified 96 RCTs; comprising of 49 trials on CHM treatment, 44 trials on acupuncture treatment and 3 trials on combined therapy for appraisal. There were 4,861 subjects in the treatment groups and 3,821 in the control groups, with treatment duration ranging from 2 weeks to 4 months. Of the 77 publications written in Chinese, 75 had a Jadad score <3, while 16 of the 19 English publications had a Jadad score of >3. Efficacy was defined as body weight reduction ≥2 kg or body mass index (BMI) reduction ≥0.5 kg/m2. Compared with placebo or lifestyle modification, CHM and acupuncture exhibited respective ‘risk ratio’ (RR) of 1.84 (95% CI: 1.37–2.46) and 2.14 (95% CI: 1.58–2.90) in favour of body weight reduction, with a mean difference in body weight reduction of 4.03 kg (95% CI: 2.22–5.85) and 2.76 kg (95% CI: 1.61–3.83) and a mean difference in BMI reduction of 1.32 kg m–2 (95% CI: 0.78–1.85) and 2.02 kg m–2 (95% CI: 0.94–3.10), respectively. Compared with the pharmacological treatments of sibutramine, fenfluramine or orlistat, CHM and acupuncture exhibited an RR of 1.11 (95% CI: 0.96–1.28) and 1.14 (95% CI: 1.03–1.25) in body weight reduction, mean difference in body weight reduction of 0.08 kg (95% CI: −0.58 to 0.74) and 0.65 kg (95% CI: −0.61 to 1.91), and mean difference in BMI reduction of 0.18 kg m–2 (95% CI: −0.39 to 0.75) and 0.83 kg m–2 (95% CI: 0.29–1.37), respectively. There were fewer reports of adverse effects and relapses of weight regain in CHM intervention studies conducted in China than studies conducted outside China. CHM and acupuncture were more effective than placebo or lifestyle modification in reducing body weight. They had a similar efficacy as the Western anti‐obesity drugs but with fewer reported adverse effects. However, these conclusions were limited by small sample size and low quality of methodologies.

Up-regulated pancreatic tissue microRNA-375 associates with human type 2 diabetes through beta-cell deficit and islet amyloid deposition.

Objectives: The aim of this study was to examine correlations of the islet-specific microRNA-375 expression to islet amyloid formation and pancreatic islet damage in human type 2 diabetes. Methods: Autopsy pancreas samples from 40 type 2 diabetic and 15 nondiabetic patients were used to detect microRNA-375 expression using real-time quantitative polymerase chain reaction. Serial paraffin sections of the corresponding type 2 diabetic and nondiabetic cases were stained by immunofluorescence to evaluate for amylin expression, amyloid formation, and proportions of &agr; and &bgr; cells. Results: Pancreatic microRNA-375 expression was increased in type 2 diabetic patients comparing with the nondiabetic patients (median, 4.02 for the diabetic patients vs 0.92 for the nondiabetic patients; P = 0.0001). The median was 6.14 for the diabetic patients with islet amyloid and 3.51 for islet amyloid-free diabetic patients. The expression level of microRNA-375 correlated positively with the frequency and the severity of islet amyloid formation and negatively with proportions of islet &bgr;-cells and amylin-positive area, and islet mitochondria density. Conclusions: Up-regulated microRNA-375 is associated with type 2 diabetes and pancreatic islet amyloid formation and &bgr;-cell deficit. microRNA-375 may serve as a biomarker for known and novel pathways in the pathogenesis of type 2 diabetes related to islet amyloid deposition and &bgr;-cell dysfunction.

Phycocyanin protects INS-1E pancreatic beta cells against human islet amyloid polypeptide-induced apoptosis through attenuating oxidative stress and modulating JNK and p38 mitogen-activated protein kinase pathways

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.

Involvement of mitochondrial dysfunction in human islet amyloid polypeptide-induced apoptosis in INS-1E pancreatic beta cells: An effect attenuated by phycocyanin

Misfolded human islet amyloid polypeptide (hIAPP) in pancreatic islets is associated with the loss of insulin-secreting beta cells in type 2 diabetes. Insulin secretion impairment and cell apoptosis can be due to mitochondrial dysfunction in pancreatic beta cells. Currently, there is little information about the effect of hIAPP on mitochondrial function. In this study, we used INS-1E rat insulinoma beta cells as a model to investigate the role of mitochondria in hIAPP-induced apoptosis and the protective effects of phycocyanin (PC). We demonstrated that hIAPP induced apoptosis in INS-1E cells was associated with the disruption of mitochondrial function, as evidenced by ATP depletion, mitochondrial mass reduction, mitochondrial fragmentation and loss of mitochondrial membrane potential (ΔΨ(m)). Further molecular analysis showed that hIAPP induced changes in the expression of Bcl-2 family members, release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytosol, activation of caspases and cleavage of poly (ADP-ribose) polymerase. Interestingly, the hIAPP-induced mitochondrial dysfunction in INS-1E cells was effectively restored by co-treatment of PC. Moreover, there was crosstalk between the extrinsic and intrinsic apoptotic pathways as demonstrated by cleavage of Bid by caspase-8 in the apoptotic process triggered by hIAPP. Taken together, we demonstrated for the first time the involvement of mitochondrial dysfunction in hIAPP-induced INS-1E cell apoptosis. Attenuation of mitochondrial dysfunction provides a mechanism for the protective effects of PC.

Bip overexpression, but not CHOP inhibition, attenuates fatty-acid-induced endoplasmic reticulum stress and apoptosis in HepG2 liver cells

AIMS In this study we investigated whether attenuation of endoplasmic reticulum stress (ER stress) could protect HepG2 cells from free fatty acid (FFA)-induced apoptosis. MAIN METHODS Human liver cell line HepG2 cells were exposed to Sodium Palmitate (Pa) or Sodium Oleate (Ol). Apoptosis and ER stress of HepG2 cells were analyzed with flow cytometry, real-time RT-PCR and Western Blotting. An expression plasmid encoding for the ER chaperone immunoglobulin heavy chain-binding protein (Bip) was transfected into HepG2 cells to attenuate ER stress. Small interfering RNA siCHOP was used to knockdown the expression of C/EBP Homologous Protein (CHOP) in HepG2. KEY FINDINGS Pa led to cytotoxicity and apoptosis in HepG2 cells in a dose-dependent pattern and also induced ER stress indicated by increased phosphorylation of eIF2α, upregulation of IRE1α and CHOP. Bip expression levels were slightly down regulated after Pa treatment. The unsaturated fatty acid, Ol, induced neither apoptosis nor ER stress in HepG2 cells. Overexpression of Bip attenuated Pa-induced ER stress and led to a significant reduction in Pa-mediated apoptosis, indicating a requirement of ER stress for lipotoxicity in liver cells. siRNA-mediated reduction of CHOP did not protect against Pa-induced apoptosis. SIGNIFICANCE While ER stress makes a necessary contribution to palmitate cytotoxicity, inhibition of CHOP alone is not sufficient to prevent palmitate-induced apoptosis. Our findings could advance the detailed understanding on the mechanism of high fatty acid (FFA)-induced apoptosis.

Fat redistribution and adipocyte transformation in uninephrectomized rats.

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.

Low LDL Cholesterol, Albuminuria, and Statins for the Risk of Cancer in Type 2 Diabetes: The Hong Kong Diabetes Registry

OBJECTIVE LDL cholesterol <2.80 mmol/l was associated with increased cancer risk in type 2 diabetes. We explored the 1) interaction between low LDL cholesterol and albuminuria and 2) interaction between copresence of these two risk factors and statin use for cancer in type 2 diabetes. RESEARCH DESIGN AND METHODS We analyzed prospective data for 3,793 Chinese type 2 diabetic patients who remained naive for statin treatment and 1,483 patients in whom statin treatment was initiated during a median follow-up period of 5.24 years. All patients were free of cancer at baseline. Biological interactions were estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RERI > 0, AP > 0, or S > 1 indicates biological interaction. RESULTS In 3,793 statin-naive type 2 diabetic patients, copresence of low LDL cholesterol and albuminuria increased cancer risk by 2.8-fold (hazard ratio 2.77 [95% CI 1.78–4.31]) with significant biological interactions (RERI 1.05 [0.04–2.06]; AP 0.38 [0.09–0.66]). In the whole cohort of 5,276 type 2 diabetic patients, there was interaction between nonuse of statins and copresence of low LDL cholesterol and albuminuria with increased cancer risk (RERI 2.87 [0.64–5.09] and AP 0.60 [0.29–0.90]). Statin nonusers with LDL cholesterol <2.80 mmol/l and albumunuria had a 4.9-fold risk of cancer compared with statin users with or without both risk factors. CONCLUSIONS In type 2 diabetes, there was interaction between low LDL cholesterol and albuminuria with increased cancer risks. The latter was attenuated in the presence of statin treatment.

Amyloid oligomers in diabetic and nondiabetic human pancreas

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.

Additive Interaction Between the Renin-Angiotensin System and Lipid Metabolism for Cancer in Type 2 Diabetes

OBJECTIVE Clinical and experimental studies suggest cross-talk between lipid metabolism and the renin-angiotensin system (RAS) in atherogenesis. The aim of this study was to explore interactions between these two systems in mediating cancer risk in type 2 diabetes. RESEARCH DESIGN AND METHODS A prospective cohort of 4,160 Chinese patients with type 2 diabetes, free of cancer at enrollment, were analyzed using Cox models. Interaction of RAS inhibitors (angiotensin I–converting enzyme inhibitors or angiotensin II receptor blockers) and statins was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index (S). RERI > 0, AP > 0, or S > 1 indicates additive interaction between the two classes of drugs. Molecular mechanisms underlying these interactions were explored using a uninephrectomy (UNX) rat model with renal carcinogenesis. RESULTS During 21,992 person-years of follow-up, 190 patients developed cancer. Use of RAS inhibitors and statins in isolation or combination during follow-up was associated with reduced risk of cancer after adjustment for covariates. The multivariable RERI and AP for the additive interaction between these drug classes for cancer were significant (0.53 [95% CI 0.20–0.87] and 2.65 [0.38–4.91], respectively). In the UNX rat model, inhibition of the RAS prevented renal cell carcinoma by normalizing hydroxymethylglutaryl-CoA reductase (HMGCR) expression and the insulin-like growth factor-1 (IGF-1) signaling pathway. CONCLUSIONS Combined use of RAS inhibitors and statins may act synergistically to reduce cancer risk, possibly via HMGCR and IGF-1 signaling pathways in high-risk conditions such as type 2 diabetes.