Fang Zhang

PPARδ Activation Rescues Pancreatic β-Cell Line INS-1E from Palmitate-Induced Endoplasmic Reticulum Stress through Enhanced Fatty Acid Oxidation

One of the key factors responsible for the development of type 2 diabetes is the loss of functional pancreatic β cells. This occurs due to a chronic exposure to a high fatty acid environment. ER stress is caused by an accumulation of irreversible misfold or unfold protein: these trigger the death of functional pancreatic β cells. PPARδ is an orphan nuclear receptor. It plays a pivotal role in regulating the metabolism of dietary lipids and fats. However, the correlation between PPARδ of fatty acids and ER stress of pancreatic β cells is not quite clear till date. Here, we show that PPARδ attenuates palmitate-induced ER stress of pancreatic β cells. On the other hand, PPARδ agonist inhibits both abnormal changes in ER structure and activation of signaling cascade, which is downstream ER stress. Further, we illustrate that PPARδ attenuates palmitate-induced ER stress by promoting fatty acid oxidation through treatment with etomoxir, an inhibitor of fatty acid oxidation. It dramatically abolishes PPARδ-mediated inhibition of ER stress. Finally, we show that PPARδ could protect pancreatic β cells from palmitate-induced cell death and dysfunction of insulin secretion. Our work elucidates the protective effect of PPARδ on the fatty-acid-induced toxicity of pancreatic β cells.

Cardiovascular effects of dipeptidyl peptidase-4 inhibitor in diabetic patients with and without established cardiovascular disease: a meta-analysis and systematic review

ABSTRACT Objectives: We aim to conduct a meta-analysis, by stratifying diabetic patients with or without clinical cardiovascular diseases (CVD), to explore whether there are different cardiovascular effects of dipeptidyl peptidase-4 inhibitors (DPP-4is) on these two different classes of diabetic patients. Methods: We searchedMedline,Embase, theCochrane Libraryand ClinicalTrials.gov for relevant randomized controlled trials (RCTs). The included trials are divided into CVD (+) trials (subjects with established CVD), and CVD (-) trials (subjects with no CVD). We use all-cause mortality and cardiovascular outcomes as primary endpoints. Results: (1) Three CVD (+) trials were included and 36,895 subjects were enrolled with a mean follow-up duration of 127.1 weeks. The pooled results showed that DPP-4is treatment, compared with the placebo, did not significantly affect all-cause mortality (RR, 1.03; 95% CI, 0.95 to 1.11), cardiovascular death (1.01, 0.91 to 1.12), myocardial infarction (0.98, 0.88 to 1.08) or stroke (1.02, 0.88 to 1.18) in diabetic patients with coexisting CVD history; however, it significantly increased the risk of heart failure (1.14, 1.01 to 1.27) in this population. 2) Thirty-five CVD (-) trials were included, and 29,600 patients were enrolled with a mean follow-up duration of 77.8 weeks. The analysis comparing DPP-4is with the placebo control showed that DPP-4is treatment did not significantly affect the risk of all-cause mortality or cardiovascular outcomes in diabetic patients free of CVD history. However, when compared with the active control, the pooling data showed that DPP-4is had a significant reduction on the risk of stroke (0.58, 0.34 to 0.99) but did not significantly affect the risk of all-cause mortality and other cardiovascular outcomes. Conclusion: DPP-4is may have no cardiovascular protective effects in diabetic patients with coexisting CVD, while there is a lack of definitive evidence supporting the cardiovascular benefits of DPP-4is treatment among diabetic patients free of CVD history.

The association of visceral adipose tissue and subcutaneous adipose tissue with metabolic risk factors in a large population of Chinese adults.

Abdominal visceral (VAT) and subcutaneous (SAT) adipose tissues contribute to obesity, but may have different cardiometabolic risk profiles. We examined and compared the associations of abdominal VAT and SAT with metabolic risk factors in a large cohort of Chinese adults.

Efficacy and safety of glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVEnNew drugs are urgently needed for the treatment of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The aim of this meta-analysis was to evaluate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in NAFLD/NASH.nnnMETHODSnWe searched the MEDLINE, Embase, and Cochrane Library Central to identify randomized controlled trials (RCTs) and observational studies that compared GLP-1RAs with a control treatment or baseline values with respect to efficacy and safety in patients with NAFLD/NASH. Mean differences (MDs) with 95% confidence intervals (CIs) and odds ratios (ORs) were pooled using a random-effect model.nnnRESULTSnSix studies were eligible and included. Among the 329 NAFLD/NASH patients included in these studies, 277 patients had type 2 diabetes (T2D). GLP-1RA treatment produced significant reductions relative to baseline in liver histology scores for steatosis (MD, 0.80; 95% CI, 0.49 to 1.11), lobular inflammation (MD, 0.22; 95% CI, 0.00 to 0.45), hepatocellular ballooning (MD, 0.41; 95% CI, 0.15 to 0.67) and fibrosis (MD, 0.35; 95% CI, 0.00 to 0.70). Compared with placebo and positive agents, GLP-1RAs significantly reduced gamma-glutamyl transpeptidase (GGT) levels (MD, 13.8 U/L; 95% CI, 7.4 to 20.3; P<0.001). The reported major adverse events associated with GLP-1RA treatment included mild to moderate gastrointestinal discomfort that resolved within a few weeks.nnnCONCLUSIONSnOur study suggests that in NASH patients, particularly patients with diabetes, GLP-1RAs may improve liver histology and reduce aminotransferase levels from baseline. Benefits of GLP-1RAs are considered to outweigh the risks in NAFLD/NASH patients with or without diabetes.

Effects on All-cause Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes by Comparing Insulin With Oral Hypoglycemic Agent Therapy: A Meta-analysis of Randomized Controlled Trials

PURPOSEnRetrospective, case-control studies and prospective randomized controlled trials (RCTs) on insulin treatment for diabetic patients yielded contradictory mortality and cardiovascular outcomes. We aimed to evaluate the effects of insulin versus oral hypoglycemic agents (OHAs) on all-cause mortality and cardiovascular outcomes in patients with type 2 diabetes (T2D).nnnMETHODSnWe searched Medline, Embase, Cochrane Central Register of Controlled Trials, Chinese Biological Medicine Database, China National Knowledge Infrastructure, Chinese Technical Periodicals, and Wanfang Data, up to July 10, 2015, for RCTs on insulin and OHAs that assessed all-cause mortality and/or cardiovascular death as primary end points. We derived pooled risk ratios (RRs) as summary statistics.nnnRESULTSnThree trials were included in which 7649 patients received insulin and 8322 received OHAs, with mean (SD) diabetes duration of 5.0 (6.2) and 4.4 (5.9) years, respectively. Insulin did not differ from OHAs in all-cause mortality (RR = 1.00; 95% CI, 0.93-1.07), cardiovascular death (RR = 1.00; 95% CI, 0.91-1.09), myocardial infarction (RR = 1.04; 95% CI, 0.93-1.16), angina (RR = 0.97; 95% CI, 0.88-1.06), sudden death (RR = 1.02; 95% CI, 0.66-1.56), or stroke (RR = 1.01; 95% CI, 0.88-1.15). Insulin reduced the risk of heart failure compared with OHAs (RR = 0.87; 95% CI, 0.75-0.99). In the subgroup of secondary prevention of cardiovascular diseases (CVDs) or very high risk of CVDs, insulin did not differ from OHAs in all-cause mortality (RR = 0.99; 95% CI, 0.92-1.07), cardiovascular death (RR = 0.99; 95% CI, 0.90-1.09), myocardial infarction (RR = 1.01; 95% CI, 0.88-1.15), heart failure (RR = 0.69; 95% CI, 0.34-1.40), or stroke (RR = 1.05; 95% CI, 0.90-1.21).nnnIMPLICATIONSnInsulin did not provide a clear benefit over OHAs in all-cause mortality or cardiovascular outcomes in the patients with T2D. Insulin therapy has many shortcomings, including inconvenience (injection, strict blood glucose monitoring), hypoglycemia, and obvious weight gain. Thus, we conclude that no robust evidence supports the active use of insulin for this population at present.

Circulating mesencephalic astrocyte-derived neurotrophic factor is increased in newly diagnosed prediabetic and diabetic patients, and is associated with insulin resistance

Evidence has shown that endoplasmic reticulum (ER) stress was involved in the progression to type 2 diabetes mellitus (T2DM) and development of insulin resistance. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel secreted protein upregulated by ER stress. This study aimed to assess serum level of MANF in normal glucose tolerance (NGT) participants and newly diagnosed prediabetic and T2DM patients. A total of 257 participants with NGT, newly diagnosed prediabetes or T2DM were recruited from Yinchao and Hangtian communities of Chengdu, Sichuan, China. Serum MANF level was quantified by enzyme-linked immunosorbent assay (ELISA). The mean age for the 257 participants (147 females) was 62±8 years (range 44-78): 71 with NGT, 115 with newly diagnosed prediabetes and 71 with T2DM. Mean serum MANF level was significantly higher with newly diagnosed prediabetes and T2DM than NGT (2.89±1.09 and 3.03±1.73 vs 2.13±1.37 ng/mL, both p<0.001). MANF level was not correlated with insulin sensitivity indexes (homeostasis model assessment for insulin resistance [HOMA-IR], Matsuda Index and quantitative insulin sensitivity check index [QUICKI]) for NGT and T2DM participants but was correlated with such indexes for prediabetes patients. We concluded that serum MANF level was higher in patients with newly diagnosed prediabetes and T2DM than in NGT controls. MANF appears to be associated with Matsuda Index, QUICKI and HOMA-IR in prediabetes patients.

Legacy Effect of Intensive Blood Glucose Control on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Very High Risk or Secondary Prevention of Cardiovascular Disease: A Meta-analysis of Randomized Controlled Trials

PURPOSEnWe performed a meta-analysis to investigate the legacy effect of >5 years of intensive blood glucose lowering on cardiovascular outcomes in patients with type 2 diabetes and very high risk or secondary prevention of cardiovascular disease (CVD).nnnMETHODSnWe mainly searched PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials. Patients in the included studies had intensive glucose lowering for >5 years and posttrial follow-up for at least 5 years. Primary end points were all-cause mortality and cardiovascular death. Secondary end points were major macrovascular events, myocardial infarction, and stroke. We used risk ratios (RRs) with 95% CIs as summary statistics.nnnFINDINGSnWe included 3 trials that involved 13,684 patients, of whom 6805 received intensive glucose-lowering treatment and 6879 received standard treatment. The mean total follow-up duration was 10.3 years, which included 5.4 years of in-trial intervention and 5.5 years of posttrial follow-up. Intensive glucose control treatment did not significantly reduce all-cause mortality (RR = 0.98; 95% CI, 0.87-1.10) or cardiovascular death (RR = 0.97; 95% CI, 0.87-1.09). No significant risk reduction was found for stroke (RR = 1.02; 95% CI, 0.92-1.14), myocardial infarction (RR = 0.91; 95% CI, 0.75-1.09), or major macrovascular events (RR = 0.99; 95% CI, 0.93-1.06).nnnIMPLICATIONSnA legacy effect of >5-year intensive blood glucose control on cardiovascular outcomes in patients with type 2 diabetes and very high risk or secondary prevention of CVD was not detected, although this effect might be applicable in patients with diabetes and primary prevention of CVD. Further investigation of the legacy effect in different CVD risk populations should therefore be performed.

The MTMR9 rs2293855 polymorphism is associated with glucose tolerance, insulin secretion, insulin sensitivity and increased risk of prediabetes

BACKGROUNDnPolymorphism of rs2293855 in gene MTMR9 has been associated with obesity and metabolic syndrome. We aim to study the association of rs2293855 with type 2 diabetes mellitus (T2DM) intermediate phenotypes in a Han Chinese population.nnnMETHODSnThe polymorphism was genotyped in 838 Han Chinese individuals using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent a 75 g oral glucose tolerance test (OGTT); associations between the polymorphism and glucose tolerance, indices of insulin secretion and indices of insulin sensitivity were analyzed.nnnRESULTSnThe frequency of genotypes and alleles differed significantly between normal glucose tolerance and prediabetes (P=0.043 and P=0.009, respectively). The GG homozygous presented higher fasting plasma glucose (P=0.009), higher 2-hour plasma glucose (P=0.024) and higher glucose area under the curve (AUC, P=0.01). Moreover, the G allele of rs2293855 was associated with glucose intolerance (fasting glucose, P=0.012; glucose AUC, P=0.006; 2-h glucose, P=0.024); it is also associated with decreased indices of insulin sensitivity (fasting insulin, P=0.043; insulin sensitivity index composite, P=0.009; homeostasis model assessment of insulin resistance, HOMA-IR, P=0.008) and decreased indices of insulin secretion (HOMA of beta cell function, HOMA-B, P=0.028; insulinogenic index, P=0.003). In addition, the minor allele G was also associated with increased risk of prediabetes (OR=1.463, 95%CI: 1.066-2.009, P=0.018).nnnCONCLUSIONSnPolymorphism of rs2293855 in MTMR9 is associated with measures of glucose tolerance, indices of insulin secretion and indices of insulin sensitivity. We also suggest that allele G is likely to increase the risk of prediabetes by influencing both insulin secretion and insulin sensitivity.

Consideration of the diagnosis of hypertension accompanied with hypokalaemia: monism or dualism?

This case report describes a 53-year-old male patient with persistent hypertension and hypokalaemia. Laboratory tests showed that the patient had hypokalaemia, hypocalcaemia and reduced urine calcium/creatinine. Levels of aldosterone and renin activity were increased significantly. Serum levels of adrenocorticotropic hormone, plasma total cortisol level, 24-h urinary-free cortisol, catecholamines, thyroid stimulating hormone and free tetraiodothyronine were normal. A novel single heterozygous mutation (c.836T> G [E6]) was found after full sequencing of the solute carrier family 12 member 3 (SLC12A3) gene exons. The patient was diagnosed as having primary hypertension with Gitelman syndrome (GS). These findings triggered the careful consideration of whether a monistic or dualist approach to the diagnosis of this patient was the most appropriate. Monism may not always be the most appropriate approach for the diagnosis of coexistent hypertension and hypokalaemia. Consideration should be given to the possibility of the independent existence of distinct diseases (i.e. dualism) when secondary hypertension cannot be confirmed by conventional examinations and when a genetic diagnosis is crucial. As a common cause of hypokalaemia with a high level of clinical phenotypic variation, GS does not conform to the usual diagnostic criteria. It should also be noted that single heterozygous SLC12A3 gene mutations can cause disease symptoms and other genetic mutations might be involved in the pathogenesis of GS.

Evaluation of the HbA1c Reduction Cut Point for a Nonglycemic Effect on Cardiovascular Benefit of Hypoglycemic Agents in Patients with Type 2 Diabetes Based on Endpoint Events

Background Atherosclerotic cardiovascular disease (ASCVD) is a major cause of death among patients with diabetes but can be improved by certain hypoglycemic agents. However, adjudicating criteria on whether improvements are a glycemic or nonglycemic effect of these agents remain unclear. Methods Hypoglycemic agents that produce a cardiovascular benefit in nondiabetic patients are considered to do so via a nonglycemic effect. We performed a subgroup analysis for primary and secondary prevention or very high risk of ASCVD in patients with type 2 diabetes (T2DM). Where glycosylated hemoglobin (HbA1c) was reduced to the same extent in a head-to-head comparison, cardiovascular benefits were judged as a nonglycemic effect. Furthermore, by analyzing the endpoints of four important randomized controlled intensive glucose control studies, UKPDS33, ADVANCE, ACCORD, and VADT, we calculated the cut point of HbA1c reduction for a nonglycemic effect on cardiovascular benefit by hypoglycemic agents in ASCVD groups of different severities. Results For the ASCVD primary prevention group of T2DM, UKPDS33 indicated a reduction in HbA1cu2009<u20090.9%, and a cardiovascular benefit within 10 years was considered a nonglycemic effect. For ASCVD secondary prevention or in the very high-risk group, pioglitazone exerted a nonglycemic effect on cardiovascular benefit in nondiabetic patients with insulin resistance; metformin may exert a similar effect in T2DM patients in a head-to-head study. Analysis of T2DM intensive glucose control studies showed a reduction in HbA1c of <1.0%, and a cardiovascular benefit after approximately 5 years was deemed a nonglycemic effect. Conclusions For ASCVD primary prevention in T2DM, a reduction in HbA1cu2009<u20090.9% and a cardiovascular benefit within 10 years were considered a nonglycemic effect. For ASCVD secondary prevention or in a very high-risk population, a reduction in HbA1cu2009<u20091.0% and a cardiovascular benefit within about 5 years were also considered a nonglycemic effect.