Yuwei Zhang

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.

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.

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.

Acarbose monotherapy and weight loss in Eastern and Western populations with hyperglycaemia: an ethnicity-specific meta-analysis

To demonstrate if weight loss achieved with acarbose in individuals with hyperglycaemia differs between Eastern and Western populations.

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.

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.

The association of hypernatremia and hypertonic saline irrigation in hepatic hydatid cysts: A case report and retrospective study

Rationale: Hypernatremia is a rare but fatal complication of hypertonic saline (HS) irrigation in hepatic hydatid disease. It needs careful monitoring and treatment. Patient concerns: A 28-year-old woman with hepatic hydatid cysts who received operation treatment developed electrolyte disturbances. We also conducted a retrospective study about influence of HS application on electrolytes in patients with hepatic hydatid disease receiving surgery. Diagnoses: Hypernatremia, developed after HS irrigation. Interventions: Normal saline, 5% dextrose and other supportive treatment were administered. In the retrospective study, a comparison of electrolyte and glucose fluctuation was made among different HS application groups. Outcomes: The patient developed hypernatremia after irrigation with HS and died from severe complications. Although some cases of complications are found, no significant relationship between HS irrigation and hypernatremia was reported according to the retrospective study. Lessons: Hypernatremia after HS irrigation remains rare but might cause severe complications. Monitoring and appropriate treatment are needed to improve prognosis.

A novel homozygous mutation in the solute carrier family 12 member 3 gene in a Chinese family with Gitelman syndrome

Loss of function of mutated solute carrier family 12 member 3 (SLC12A3) gene is the most frequent etiology for Gitelman syndrome (GS), which is mainly manifested by hypokalemia, hypomagnesemia and hypocalciuria. We report the genetic characteristics of one suspicious Chinese GS pedigree by gene sequencing. Complete sequencing analysis of the SLC12A3 gene revealed that both the proband and his elder sister had a novel homozygous SLC12A3 mutation: c.2099T>C and p.Leu700Pro. Moreover, the SLC12A3 genes of his mother and daughter encoded the same mutated heterozygote. It was noted that in this pedigree, only the proband complained about recurrent episodes of bilateral lower limb weakness over 8 years, while his elder sister, mother and daughter did not present symptoms. The inconsistent clinical features of this pedigree implied that besides diverse phenotypes possibly originated from the same genotype, gender difference may also dominate the variant GS phenotypes. Further genetic and proteomic research are needed to investigate the precise mechanisms of GS, including the study of specific ethnicities.