Qingguo Lü

Activation of PPARδ up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic β-cells

Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor delta (PPARdelta) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic beta-cells. After HIT-T15 cells (a beta-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPARdelta), we found that administration of GW increased the expression of PPARdelta mRNA. GW-induced activation of PPARdelta up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPARdelta plays an important role in protecting pancreatic beta-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

Impaired Secretion of Total Glucagon-like Peptide-1 in People with Impaired Fasting Glucose Combined Impaired Glucose Tolerance

Objective: We assessed the serum glucagon-like peptide-1 (GLP-1) levels for Chinese adults with pre-diabetes (PD) and newly-diagnosed diabetes mellitus (NDDM) during oral glucose tolerance test (OGTT). The relationships between total GLP-1 level and islet β cell function, insulin resistance (IR) and insulin sensitivity (IS) were also investigated. Methods: A 75g glucose OGTT was given to 531 subjects. Based on the results, they were divided into groups of normal glucose tolerance (NGT), isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined IGT (IFG+IGT) and NDDM. Total GLP-1 levels were measured at 0- and 2-hour during OGTT. Homeostasis model assessment of β cell function (HOMA-β), HOMA of insulin resistance (HOMA-IR), Gutt and Matsuda indexes were calculated. The relationships between GLP-1 level and β cell function, IR and IS were analyzed. Results: The levels of total fasting GLP-1 (FGLP-1), 2h GLP-1 (2hGLP-1) and 2hGLP-1 increments (∆GLP-1) following OGTT reduced significantly in IFG+IGT and NDDM groups (P<0.005). HOMA-β , HOMA-IR, Gutt and Matsuda indexes demonstrated various patterns among NGT, isolated IFG, isolated IGT, IFG+IGT and NDDM groups (P<0.05). Spearman rank correlation analysis and multivariable linear regression model suggested that some levels of correlation between GLP-1 levels, ∆GLP-1 and β cell function, IR (P<0.05). Conclusions: The total GLP-1 levels and its response to glucose load decreased significantly in IFG+IGT group, compared to isolated IFG or IGT group. They were even similar to that of NDDM group. Moreover, there were observable correlations between impaired GLP-1 secretion and β cell function, IR and IS.

Activation of PPARδ promotes mitochondrial energy metabolism and decreases basal insulin secretion in palmitate-treated β-cells

The peroxisome proliferator-activated receptor δ (PPARδ) regulates the expression of genes involved in cellular lipid and cell energy metabolism in many metabolically active tissues, such as liver, muscle, and fat, and plays a role in the cellular response to stress and environmental stimuli. The particular role of PPARδ in insulin-secreting β-cells, however, is not well understood; we recently identified the cell-specific role of PPARδ on mitochondrial energy metabolism and insulin secretion in lipotoxic β-cells. After treatment of HIT-T15 cells, a syrian hamster pancreatic β-cell line, with high concentrations of palmitate and/or the specific PPARδ agonist GW501516, we detected the gene expression changes for transcripts, such as peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1α), nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (mtTFA), the protein levels of the mitochondria uncoupling protein 2 (UCP2), mitochondrial morphology, the insulin secretion capacity and ATP/ADP ratio. Our results show that GW501516 treatment promoted generation of mitochondrial ATP, as well as expression levels of PGC-1α, NRF-1 and mtTFA, decreased basal insulin secretion, but had no effect on glucose-stimulated insulin secretion (GSIS), increased amounts of UCP2 and changed ATP-to-ADP ratio, improved mitochondrial morphology in palmitate-treated β-cells. GW501516-induced activation of PPARδ enhanced mitochondrial energy metabolism, but also promoted a concomitant mitochondrial uncoupling and resulted in decreased basal insulin secretion and restricted GSIS; this observation indicated the possible action of a protective mechanism responding to the alleviation of excessive lipid load and basal insulin secretion in lipotoxic β-cells.

Community-based population data indicates the significant alterations of insulin resistance, chronic inflammation and urine ACR in IFG combined IGT group among prediabetic population

AIMS To investigate alterations of insulin resistance (IR), chronic inflammation and urine albumin-to-creatinine ratio (ACR) in Chinese community-based prediabetic population. MATERIALS AND METHODS 252 prediabetics [prediabetes (PD), including impaired fasting glucose (IFG), 91; impaired glucose tolerance (IGT), 123; IFG+IGT, 38] and 38 newly diagnosed-diabetics (NDDM) aged over 35 years older were screened from 2336 community individuals. 123 age and gender matched individuals with normal glucose tolerance (NGT) were selected as controls. Serum adiponectin, interleukin-6 (IL-6) levels and urine ACR were determined, HOMA-IR and Gutts index were calculated to evaluate IR and insulin sensitivity, respectively. RESULTS The data displayed significant difference of serum adiponectin, IL-6, ACR and Gutts index among PD, NDDM and NGT groups. Adiponectin level and Gutts index decreased, but IL-6 level and ACR increased gradually among NGT, PD and NDDM groups (P<0.01). Unlike adiponectin and IL-6, ACR analysis indicates a gradual increase from NGT, IFG, IGT, IFG+IGT to NDDM individuals (P<0.01). Gutts index showed significant difference between IFG and NDDM, IFG+IGT and NDDM (P<0.01), but HOMA-IR index did not. CONCLUSIONS IR, chronic inflammation and endothelial dysfunction dose exist in prediabetic individuals, especially in IFG+IGT population. Gutts index and ACR might seem to be more sensitive than adiponectin and HOMA-IR index as IR and chronic inflammation maker in prediabetic population.

PPARD rs2016520 polymorphism is associated with metabolic traits in a large population of Chinese adults.

AIMS Polymorphism of rs2016520 in gene PPARD has been associated with lipid metabolism, obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). We aimed to study the association of rs2016520 with common metabolic traits in a large population of Han Chinese adults. METHODS The polymorphism was genotyped in 1409 subjects using Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS); all participants underwent standard clinical examination and a 75g oral glucose tolerance test (OGTT); associations between the polymorphism and metabolic traits and indices of insulin resistance and insulin sensitivity were analyzed. RESULTS There was no significant difference in genotypes between the normal glucose tolerance (NGT) and the prediabetes group (χ(2)=3.17, P=0.2), except a nominal difference of allele frequency (χ(2)=3.07, P=0.07). The G carrier presented lower fasting plasma glucose (FPG, P=0.03), lower 2h plasma glucose (Pdom=0.04) and lower fasting insulin (P=0.02), lower systolic blood pressure (SBP, P=0.03), lower HOMA-IR (P=0.02) and higher QUICKI (P=0.01). Moreover, rs2016520 polymorphism was associated with FPG (β=-0.09, P=0.05), it was also associated with indices of insulin resistance (HOMA-IR, β=-0.06, Pdom=0.02; fasting insulin, β=-0.04, P=0.02) and indices of insulin sensitivity (QUICKI, β=-0.01, P=0.004). In addition, we observed that the allele G was also associated with lower SBP (β=-1.29, P=0.04) and diastolic blood pressure (DBP, β=-0.09, P=0.01). However, the minor allele G was not associated with risk of metabolic disorders including prediabetes, overweight, hypertension and metabolic syndrome. CONCLUSIONS Polymorphism of rs2016520 in gene PPARD was associated with benign metabolic traits in a large cohort of Chinese adults. The G allele may confer protection from type 2 diabetes and hypertension in Han Chinese.

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

BACKGROUND Polymorphism 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. METHODS The 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. RESULTS The 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). CONCLUSIONS Polymorphism 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.

Associations of the PTEN -9C>G polymorphism with insulin sensitivity and central obesity in Chinese.

BACKGROUND Phosphatase and tensin homolog on chromosome 10 gene (PTEN) is known as a tumor-suppressor gene. Previous studies demonstrated that PTEN dysfunction affects the function of insulin. However, investigations of PTEN single nucleotide polymorphisms (SNPs) and IR-related disease associations are limited. The aim of the present study was to investigate whether its polymorphism could be involved in the risk of metabolic syndrome (MetS). METHODS The genotype frequency of PTEN -9C>G polymorphism was determined by using a Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) method in 530 subjects with MetS and 202 healthy control subjects of the Han Ethnic Chinese population in a case-control analysis. RESULTS The PTEN -9C>G polymorphism was not associated with MetS or its hyperglycemia, hypertension and hypertriglyceridemia components. In the control individuals aged <60 years or ≥60 years, the CG genotype individuals had lower insulin sensitivity than CC individuals (P<0.05). In the <60-year-old MetS group and normal glucose tolerance (NGT) subgroup, the CG individuals had lower insulin sensitivity and higher waist circumference (WC) and waist-height-ratio (WHtR) than CC individuals (P<0.05). Multiple linear regression analysis showed that the PTEN polymorphism (P=0.001) contributed independently to 4.2% (adjusted R(2)) of insulin sensitivity variance (estimated by Matsuda ISI), while age (P=0.004), gender (P=0.000) and the PTEN polymorphism (P=0.032) contributed independently to 5.6% (adjusted R(2)) of WHtR variance. CONCLUSIONS The CG genotype of PTEN -9C>G polymorphism was not associated with MetS and some of its components as well. However, it may not only decrease insulin sensitivity in the healthy control and MetS in pre-elderly or NGT subjects, but may also increase the risk of central obesity among these MetS individuals.

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.

Identical anthropometric characteristics of impaired fasting glucose combined with impaired glucose tolerance and newly diagnosed type 2 diabetes: anthropometric indicators to predict hyperglycaemia in a community-based prospective cohort study in southwest China

Objectives To assess the anthropometric characteristics of normoglycaemic individuals who subsequently developed hyperglycaemia, and to evaluate the validity of these measures to predict prediabetes and diabetes. Design A community-based prospective cohort study. Participants In total, 1885 residents with euglycaemia at baseline from six communities were enrolled. Setting Sichuan, southwest China. Primary outcome measures The incidences of prediabetes and diabetes were the primary outcomes. Methods The waist-to-height ratio (WHtR), body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) of all participants were measured at baseline and during follow-up. A 75 g glucose oral glucose tolerance test was conducted at each survey. Results During a median of 3.00 (IQR: 2.92–4.17) years follow-up, the cumulative incidence of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT), IFG combined with IGT (IFG+IGT), and newly diagnosed diabetes mellitus (NDDM) were 8.44%, 18.14%, 8.06% and 13.79%, respectively. WHtR, BMI, WC and WHR were significantly different among subjects who subsequently progressed to isolated IFG or IGT, IFG+IGT or NDDM (p<0.05). The anthropometric characteristics of IFG+IGT subjects were similar to those of the NDDM population (p>0.005). All the baseline anthropometric measurements were useful for the prediction of future prediabetes and NDDM (p<0.05). The optimal thresholds for the four measurements were calculated for the prediction of hyperglycaemia, with a WHtR value of 0.52 performing best to identify isolated IFG or IGT, IFG+IGT and NDDM. Conclusions Anthropometric measures, especially WHtR, could be used to predict hyperglycaemia 3 years in advance. Distinct from isolated IFG and IGT, the individuals who developed combined IFG+IGT had identical anthropometric profiles to those who progressed to NDDM.

Glucagon-like peptide-1 mimetics, optimal for Asian type 2 diabetes patients with and without overweight/obesity: meta-analysis of randomized controlled trials

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are desirable for diabetes, especially in patients with overweight/obesity. We aimed to determine whether GLP-1RAs exhibit different glucose-lowering efficacies between Asian type 2 diabetes (T2D) patients with and without overweight/obesity. Randomized controlled trials were searched in EMBASE, MEDLINE, CENTRAL, and ClinicalTrials.gov. Studies published in English with treatment duration ≥12 weeks and information on HbA1c changes were included. The studies were divided into normal body mass index (BMI) and overweight/obese groups according to baseline BMI. Among 3190 searched studies, 20 trials were included in the meta-analysis. The standardized mean differences in HbA1c change, fasting glucose change, and postprandial glucose change were equivalent between normal BMI and overweight/obese studies (p > 0.05). The relative risk of HbA1c < 6.5% target achievement in normal BMI trials (7.93; 95% confidence interval: 3.27, 19.20) was superior to that in overweight/obesity trials (2.23; 1.67, 2.97), with a significant difference (p = 0.020). Body weight loss (p = 0.572) and hypoglycemic risk(p = 0.920) were similar in the two groups. The glucose-lowering effects of GLP-1RAs were equivalent among Asian T2D patients. With their advantages for weight-loss or weight-maintenance, GLP-1RAs are optimal medicines for Asian T2D patients with and without overweight/obesity.