Epicardial adipose tissue volume highly correlates with left ventricular diastolic dysfunction in endogenous Cushing's syndrome.

BACKGROUND: Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS: A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS: A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION: CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

This study explored the potential risk factors of LVDD in endogenous CS by incorporating body composition parameters. EATV was identified as an independent risk factor for LVDD. Targeted therapeutic interventions to reduce excessive cortisol-induced EAT accumulation may be promising to mitigate the risk of LVDD development in patients with CS.

Bilateral breast myxedema caused by Graves' disease and responsive to multipoint subcutaneous injection of long-acting glucocorticoid: Case report.

RATIONALE: With the absence of ophthalmopathy, thyroid dermopathy especially lesions at atypical locations is a very rare presentation. We herein report an original case of bilateral breast myxedema caused by Grave's disease. PATIENT CONCERNS: A 21-year-old unmarried woman presented with a 4-month history of Grave's disease and a 1-month history of progressive bilateral breast enlargement. She had symmetrical bilateral breast enlargement with redness and nonpitting thickening of the skin, diffusely enlarged thyroid glands, and no exophthalmos. DIAGNOSIS: Ultrasonography, magnetic resonance imaging scan, and skin biopsy confirmed the diagnosis of bilateral breast myxedema. INTERVENTIONS: The patient was treated with multipoint subcutaneous injections of triamcinolone acetonide in each breast every month. OUTCOMES: The bilateral breast returned approximately to its normal size after therapy for 6 months. CONCLUSIONS: Our case illustrates that multipoint subcutaneous injection of glucocorticoids is beneficial for bilateral breast myxedema.

Glycemic index, glycemic load, and glycemic response to pomelo in patients with type 2 diabetes.

Food intake has a great influence on blood glucose in patients with diabetes. This study was to determine the glycemic index (GI) and glycemic load (GL) of a particular pomelo named Majia pomelo and its effects on postprandial glucose (PPG) in patients with type 2 diabetes (T2D). Twenty healthy subjects and 20 T2D patients (controlled on lifestyle measures and/or metformin) were tested on 2 separate days with 50 g of glucose and 50 g equivalent of carbohydrates from Majia pomelo for GI measurement. To test effects of Majia pomelo on PPG, 19 hospitalized T2D patients (controlled on insulin therapy) were selected for a 9-day study. The dose of insulin for each patient was adjusted on the first 3 days. A total of 100 mg Majia pomelo was consumed per meal in the last 3 tested days. Blood glucose was measured to evaluate the glycemic excursions. The GIs for Majia pomelo in healthy individuals and T2D patients were 78.34±1.88 and 72.15±1.95 respectively. The value of GL was as low as 4.23 in diabetic patients with serving size of 100 g pomelo, indicting Majia pomelo as a high GI but low GL fruit. Consumption of Majia pomelo in hospitalized T2D patients did not cause significant glucose fluctuation. It was concluded that high GI pomelo can serve as a low GL fruit if it is consumed with a limited daily amount and thus can be supplied to diabetic patients. These results may mean more varieties of food choices for T2D patients.

Pioglitazone ameliorates Aß42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3ß activation.

Pioglitazone may have potential benefits as an alternative therapeutic treatment for patients with Alzheimer's disease (AD), particularly in individuals that also have comorbid diabetes; however, the mechanisms of action remain unclear. The present study aimed to explore the effects of pioglitazone on amyloid ß, isoform 42 (Aß42) deposition in rats with diet­induced insulin resistance (IR). Diet­induced IR model rats were established in the presence or absence of pioglitazone. Plasma glucose and insulin levels, and cerebrospinal fluid insulin levels were measured; in addition, hippocampal tissues were collected for immunohistochemical analysis of Aß42 expression. The levels of insulin­degrading enzyme (IDE) and peroxisome proliferator­activated receptor γ (PPARγ) mRNA and protein expression were analyzed by reverse transcription­quantitative polymerase chain reaction and western blotting, respectively. In addition, the activation of glycogen synthase kinase 3ß (GSK3ß) induced by phosphatidylinositol 3­kinase (PI3K) /protein kinase B (AKT) signaling was detected by western blotting. Results from the present study demonstrated that pioglitazone may enhance peripheral and brain insulin sensitivity in diet­induced IR model rats. Treatment with pioglitazone ameliorated Aß42 deposition in the hippocampus by increasing IDE and PPARγ expression. Notably, activation of the PI3K/AKT/GSK3ß pathway was also demonstrated to serve a role in pioglitazone­induced Aß42 degradation, which was abrogated by the PPARγ antagonist GW9662. Results from the present study indicated that pioglitazone may improve insulin sensitivity and ameliorate Aß42 accumulation in rats with diet­induced IR by regulating AKT/GSK3ß activation, suggesting that pioglitazone may be a promising drug for AD treatment.

17α­hydroxylase/17,20­lyase deficiency in congenital adrenal hyperplasia: A case report.

Congenital adrenal hyperplasia (CAH) is a rare autosomal recessive disorder caused by mutations in the cytochrome P450 family 17 subfamily A member 1 (CYP17A1) gene located on chromosome 10q24.3, which leads to a deficiency in 17α­hydroxylase/17,20­lyase. The disorder is characterized by low blood levels of estrogens, androgens and cortisol, which leads to a compensatory increase in adrenocorticotropic hormone levels that stimulate the production of mineralocorticoid precursors. This subsequently leads to hypertension, hypokalemia, primary amenorrhea and sexual infantilism. Over 90 distinct genetic lesions have been identified in patients with this disorder. The prevalence of common mutation of CYP17A1 gene differs among ethnic groups. Treatment of this disorder involves replacement of glucocorticoids and sex steroids. Estrogen alone is prescribed for patients who are biologically male with 17α­hydroxylase deficiencies that identify as female. However, genetically female patients may receive estrogen and progesterone supplementation. In the present study, a 17­year­old female with 17α­hydroxylase/17,20­lyase deficiency that presented with primary amenorrhea and sexual infantilism and no hypertension, was examined. The karyotype of the patient was 46, XX, and genetic analysis revealed the presence of a compound heterozygous mutation in exons 6 and 8, leading to the complete absence of 17α­hydroxylase/17,20­lyase activity. The patient was treated with prednisolone and ethinyl estradiol. In addition, a summary of the recent literature regarding CAH is presented.

Glycemic Index, Glycemic Load, and Glycemic Response to Pomelo in Patients with Type 2 Diabetes / 华中科技大学学报（医学）（英德文版）

Food intake has a great influence on blood glucose in patients with diabetes.This study was to determine the glycemic index (GI) and glycemic load (GL) of a particular pomelo named Majia pomelo and its effects on postprandial glucose (PPG) in patients with type 2 diabetes (T2D).Twenty healthy subjects and 20 T2D patients (controlled on lifestyle measures and/or metformin) were tested on 2 separate days with 50 g of glucose and 50 g equivalent of carbohydrates from Majia pomelo for GI measurement.To test effects of Majia pomelo on PPG,19 hospitalized T2D patients (controlled on insulin therapy) were selected for a 9-day study.The dose of insulin for each patient was adjusted on the first 3 days.A total of 100 mg Majia pomelo was consumed per meal in the last 3 tested days.Blood glucose was measured to evaluate the glycemic excursions.The GIs for Majia pomelo in healthy individuals and T2D patients were 78.34± 1.88 and 72.15±1.95 respectively.The value of GL was as low as 4.23 in diabetic patients with serving size of 100 g pomelo,indicting Majia pomelo as a high GI but low GL fruit.Consumption of Majia pomelo in hospitalized T2D patients did not cause significant glucose fluctuation.It was concluded that high GI pomelo can serve as a low GL fruit if it is consumed with a limited daily amount and thus can be supplied to diabetic patients.These results may mean more varieties of food choices for T2D patients.

Inhibition of 11ß-hydroxysteroid dehydrogenase type 1 ameliorates obesity-related insulin resistance.

Excess 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) may be implicated in the development of obesity related metabolic disorders. The present study measured the expression level of 11ß-HSD1 in visceral adipose tissues from 23 patients undergoing abdominal operation. Correlation of 11ß-HSD1 expression with BMI, waist-to-hip ratio (WHR), HOMA-IR, and serum lipids was evaluated by spearman correlation analysis. High-fat diet-induced obese (DIO) rats were orally dosed with BVT.2733 for 4 weeks. Weight, plasma insulin, and lipids were detected at the end of the treatment. The effects of 11ß-HSD1 inhibition on the key insulin-signaling cascade and adipocytokines were measured by western blot and ELISA respectively. 11ß-HSD1 was increased in patients with central obesity, the expression level of which was closely related with WHR (r = 0.5851), BMI (r = 0.4952), and HOMA-IR (r = 0.4637). Obesity related insulin resistance in high-fat DIO rats, as reflected by a marked decrease in IRS-1, IRS-2, GLUT4, and PI3K, could be attenuated by 11ß-HSD1 inhibition. Furthermore, the down-regulation of 11ß-HSD1 could correct the disordered profiles of adipocytokines including adiponectin, IL-6, and TNF-α. These findings indicated that 11ß-HSD1 inhibition can give a potential benefit in reducing obesity and lowering insulin resistance by modulating the insulin-signaling pathway and adipocytokine production.

Correlation of liver enzymes with diabetes and pre-diabetes in middle-aged rural population in China.

The survey aimed to explore the association of liver transaminases with the prevalence of type 2 diabetes mellitus (T2DM) and pre-diabetes (pre-DM) in the middle-aged rural population in China. A cross-sectional study was conducted in 10 800 middle-aged subjects who lived in rural area of central China. The 75-g oral glucose-tolerance test (OGTT) was performed. Participants were asked to complete physical examination and standard questionnaire. The serum liver transaminases (ALT and GGT), HbA1C and serum lipids were measured. In middle-aged rural population, the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), impaired fasting glucose combined with impaired glucose tolerance (IFG+IGT) and DM was 4.0%, 11.8%, 2.6% and 10.0%, respectively. Some measurements were higher in males than in females, such as waist hip ratio (WHR), blood pressure, fasting blood glucose (FBG), high density lipoprotein-cholesterol (HDL-C), and liver enzymes (ALT and GGT). Further, we found that elevated serum GGT and ALT levels were significantly positively correlated with the prevalence of DM, independent of central obesity, serum lipid and insulin resistance (IR) in both genders. However, the correlation of GGT and ALT with pre-DM was determined by genders and characteristics of liver enzymes. Higher serum GGT was indicative of IGT in both genders. The association of serum ALT with pre-DM was significant only in female IGT group. In conclusion, our present survey shows both serum GGT and ALT are positively associated with DM, independent of the cardiovascular risk factors in both genders.

Sclerosteosis caused by a novel nonsense mutation of SOST in a consanguineous family.

Sclerosteosis, characterized by the hyperostosis of cranial and tubular bones, is a rare autosomal recessive hereditary disorder caused by mutation of SOST gene. Four nonsense mutations of SOST have been identified worldwide. Here, we report two affected siblings who carried a novel nonsense mutation of SOST in a consanguineous family from China. The proband manifested typical symptoms of sclerosteosis, whereas the symptoms were absent in another affected sibling. Two nucleotide substitutions in exon 2 of SOST were identified, c.444_445TC>AA, resulting in a premature stop codon, p.Cys148→Stop. This truncated mutation loses 66 amino acid residues which contain 3 cysteine residues of the cysteine-knot motif, leading to loss of function of SOST. The symptoms of sclerosteosis may be clinically heterogeneous in some patients, even with the same mutation. Our results support the notion that founder effects from the ancestors contribute to the disease onset.

Glargine insulin/gliclazide MR combination therapy is more effective than premixed insulin monotherapy in Chinese patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs.

BACKGROUND: The aim of this study is to compare the efficacy and safety of once-daily insulin glargine plus gliclazide modified release combination therapy versus twice-daily premixed insulin monotherapy in Chinese type 2 diabetic patients insufficiently controlled by oral antidiabetic agents. METHODS: In a 12-week, multicenter, randomized, parallel-group clinical trial, patients with poor glycaemic control (fasting plasma glucose ≥ 7.0 mmol/L and 7.5% < haemoglobin A1c ≤ 10%) on oral antidiabetic drugs were randomized to the treatment groups for combination therapy (n = 52) or monotherapy (n = 53). Continuous glucose monitoring was carried out over two 72-h periods, at the beginning and the end of the study, and the data were used to calculate the 24-h mean blood glucose, mean amplitude of glycaemic excursions, standard deviation of blood glucose, and the mean of daily differences. RESULTS: The mean haemoglobin A1c decrease from baseline to study end was significant for both treatment groups (combination therapy: -1.23 ± 0.92%; insulin monotherapy: -1.02 ± 1.04%); moreover, the combination therapy group showed a significantly more robust haemoglobin A1c decrease (p = 0.0308). Both therapies significantly reduced the 24-h mean blood glucose (both, p < 0.001), but neither produced a significant effect on glycaemic variability, calculated as mean amplitude of glycaemic excursions, standard deviation of blood glucose, and mean of daily differences. In addition, the effects on rates of hypoglycaemic episodes were similar between the two therapies. CONCLUSIONS: Chinese patients with type 2 diabetes inadequately controlled with oral antidiabetic agents attained greater benefit from once-daily insulin glargine plus gliclazide modified release regimen than from a twice-daily premixed insulin regimen.

The changes of leukocyte telomere length and telomerase activity after sitagliptin intervention in newly diagnosed type 2 diabetes.

BACKGROUND: In recent years, increasing evidence suggests a potential importance of telomere biology in type 2 diabetes. The aim of this study was to determine whether sitagliptin, a medicine generally used in diabetes, can influence the telomere and telomerase in newly diagnosed type 2 diabetic patients. METHODS: Type 2 diabetic patients (T2D, n = 38) and non-diabetic subjects (control, n = 31) were randomly selected from the outpatient of Tongji Hospital, Tongji Medical College, Huazhong university of Science and Technology. Leukocyte telomere length ratio was measured using a quantitative polymerase chain reaction and was analysed. Telomerase activity was measured by polymerase chain reaction enzyme-linked immunosorbent assay method. Peripheral insulin resistance (homeostasis model assessment) was calculated from fasting plasma glucose and fasting plasma insulin. RESULTS: Telomere length of the type 2 diabetic patients (1.58 ± 0.57) was significantly shorter than those of control subjects (3.98 ± 0.90) and was significantly elongated after intervention by sitagliptin. There was no significant difference between the T2D and control group in telomerase activity, and the treatment of sitagliptin in T2D group showed no significant effect on the telomerase activity. CONCLUSIONS: In type 2 diabetes patients, leukocyte telomere length is significantly reduced, whereas the telomerase activity seems less influenced. Sitagliptin might protect ß-cells in the pancreas by elongating the telomere length.

Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance.

CONTEXT: Betatrophin has recently attracted increasing interests as a potential ß-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. OBJECTIVE: The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. DESIGN, SETTING, AND PARTICIPANTS: Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n = 137), isolated impaired fasting glucose (n = 69), isolated impaired glucose tolerance (n = 120), and newly diagnosed T2DM (n = 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. RESULTS: Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 ± 42.5 vs 692.7 ± 29.0, P < .05, vs 682.7 ± 43.0, P < .05, vs 646.8 ± 34.3 pg/mL, P < .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r = -0.11), the Gutt insulin sensitivity index (partial r = -0.12), and the Matsuda insulin sensitivity index (partial r = -0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P < .05). CONCLUSION: Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance.

Clinical usefulness of lipid ratios, visceral adiposity indicators, and the triglycerides and glucose index as risk markers of insulin resistance.

BACKGROUND: To directly compare traditional lipid ratios (total cholesterol [TC]/high density lipoprotein cholesterol [HDL-C], non-HDL-C/HDL-C, low density lipoprotein cholesterol [LDL-C]/HDL-C, and triglycerides [TG]/HDL-C), apolipoprotein B (apoB)/apolipoprotein A-I (apoA-I) ratio, visceral adiposity index (VAI), lipid accumulation product (LAP), and the product of TG and fasting glucose (TyG) for strength and independence as risk factors for insulin resistance (IR). METHODS: We conducted a cross-sectional analysis of 7629 Chinese adults using data from the China Health and Nutrition Survey 2009. RESULTS: For all lipid ratios (traditional lipid ratios and apoB/apoA-I), among both sexes, TG/HDL-C explained the most additional percentage of variation in HOMA-IR (2.9% in men, and 2.3% in women); for all variables of interest, the variability in HOMA-IR explained by VAI and TG/HDL-C were comparable; TyG had the most significant association with HOMA-IR, which explained 9.1% for men and 7.8% for women of the variability in HOMA-IR. Logistic regression analysis showed the similar patterns. Receiver operating characteristic (ROC) curve analysis showed that, among both sexes, TG/HDL-C was a better discriminator of IR than apoB/apoA-I; the area under the ROC curve (AUC) for VAI (0.695 in men and 0.682 in women) was greater than that for TG/HDL-C (AUC 0.665 in men and 0.664 in women); TyG presented the greatest value of AUC (0.709 in men and 0.711 in women). CONCLUSION: The apoB/apoA-I performs no better than any of the traditional lipid ratios in correlating with IR. The TG/HDL-C, VAI and TyG are better markers for early identification of IR individuals.

Secular trends in the prevalence of low risk factor burden for cardiovascular disease according to obesity status among Chinese adults, 1993-2009.

BACKGROUND: Cardiovascular disease (CVD) and obesity are now common among Chinese. We aimed to examine secular trends in the prevalence of low risk profile and to examine whether comparable changes in the prevalence of low risk profile across waist circumference (WC) groups and body mass index (BMI) categories have occurred. METHODS: We used data from the nationwide China Health and Nutrition Survey conducted in 1993, 1997, 2000, 2004, 2006, and 2009. There were 7274, 8368, 9369, 8948, 8786, and 9278 participants included in the analyses across the six study periods. We created an index of low risk factor burden from the following variables: not currently smoking, BMI < 25 kg/m2, WC < 90/80 cm in men/women, untreated systolic/diastolic blood pressure < 120/80 mmHg, and not having been previously diagnosed with diabetes. RESULTS: During the period of 1993-2009, the age-adjusted prevalence of low risk profile decreased from 16.2 to 11.5% among men and from 46.3 to 34.6% among women (both P < 0.001); Similar significant trends were observed in all age groups, rural/urban settings, education groups, WC status and BMI categories. The change in the prevalence of low risk profile was more striking among obese persons (P for interaction terms cohort *BMI were < 0.001). In 2009, 2.0 and 25.6% among central obese men and women had a low risk profile; Of note, was that 0.1 and 0.3% general obese men and women had a low risk profile. CONCLUSIONS: The prevalence of low risk profile declined considerably over the past 17 years in all demographic groups, WC status, and BMI categories. Public health prevention strategies are urgently needed.

Influence of vitamin E supplementation on glycaemic control: a meta-analysis of randomised controlled trials.

Observational studies have revealed that higher serum vitamin E concentrations and increased vitamin E intake and vitamin E supplementation are associated with beneficial effects on glycaemic control in type 2 diabetes mellitus (T2DM). However, whether vitamin E supplementation exerts a definitive effect on glycaemic control remains unclear. This article involves a meta-analysis of randomised controlled trials of vitamin E to better characterise its impact on HbA1c, fasting glucose and fasting insulin. PubMed, EMBASE and the Cochrane Library were electronically searched from the earliest possible date through April 2013 for all relevant studies. Weighted mean difference (WMD) was calculated for net changes using fixed-effects or random-effects models. Standard methods for assessing statistical heterogeneity and publication bias were used. Fourteen randomised controlled trials involving individual data on 714 subjects were collected in this meta-analysis. Increased vitamin E supplementation did not result in significant benefits in glycaemic control as measured by reductions in HbA1c, fasting glucose and fasting insulin. Subgroup analyses revealed a significant reduction in HbA1c (-0.58%, 95% CI -0.83 to -0.34) and fasting insulin (-9.0 pmol/l, 95% CI -15.90 to -2.10) compared with controls in patients with low baseline vitamin E status. Subgroup analyses also demonstrated that the outcomes may have been influenced by the vitamin E dosage, study duration, ethnic group, serum HbA1c concentration, and fasting glucose control status. In conclusion, there is currently insufficient evidence to support a potential beneficial effect of vitamin E supplementation on improvements of HbA1c and fasting glucose and insulin concentrations in subjects with T2DM.

Protective action of liraglutide in beta cells under lipotoxic stress via PI3K/Akt/FoxO1 pathway.

Liraglutide, a modified form of glucagon-like peptide-1 (GLP-1), has been found to improve beta cell function in type 2 diabetes (T2DM). However, the effect of liraglutide on beta cell function under lipotoxic stress and the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of PI3K/Akt/FoxO1 signaling in liraglutide-involved beta cell protection in high free fatty acids (FFAs) condition. The apoptosis, proliferation, and insulin secretion capability of MIN6 cells and islets from C57BL/6J mice were evaluated when exposed to FFAs with/without liraglutide. The expression of effectors involved in PI3K/Akt/FoxO1signalling pathway was detected by real-time PCR and western blotting in MIN6 cells and islets from C57BL/6J mice. Liraglutide substantially inhibited the lipoapoptosis and improved the proliferation and insulin secretion of beta cells in high FFAs condition. Western blot revealed that the phosphorylation of Akt and FoxO1 was markedly decreased under lipid stress but was elevated when treated with liraglutide. Moreover, FFAs could up-regulate the expression levels of p27, Bax, Cidea but down-regulate the expression levels of Pdx-1, MafA, and NeuroD in beta cells, which was canceled by the addition of liraglutide. Moreover, LY294002, a PI3K inhibitor, could significantly abrogate all the protective actions of liraglutide against lipotoxicity. We concluded that liraglutide markedly improved beta cell function under lipid stress and that the protective action of liraglutide was mediated by activation of PI3K/Akt, which resulted in inactivation of FoxO1 along with the down-regulation of p27, Bax, Cidea and up-regulation of Pdx-1, MafA, and NeuroD expressions.

Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes.

BACKGROUND/OBJECTIVE: Type 2 diabetes increases the risk for developing Alzheimer's disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats. METHODS: Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood, cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks. RESULTS: We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3ß (GSK-3ß) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3ß, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner. CONCLUSION: Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes.

Neutralization of interleukin-17 attenuates high fat diet-induced non-alcoholic fatty liver disease in mice.

Non-alcoholic fatty liver disease (NAFLD) is hepatic manifestation of a metabolic syndrome and includes a spectrum of hepatic steatosis, steatohepatitis, and fibrosis. Interleukin-17 (IL-17) has been reported to play a critical role in inflammatory progression of some liver diseases. The present study was designed to investigate the role of IL-17 on high fat diet-induced NAFLD in C57BL/6 mice. IL-17 blockade with anti-IL-17mAb significantly improved liver function, attenuated hepatic lipid accumulation, suppressed Kuffer cells activation, and decreased pro-inflammatory cytokines levels, which were associated with inhibition of NF-κB signaling cascades activation. Our data suggested that IL-17 was related to disease progression in NAFLD mouse model and blocking IL-17 may be a promising novel therapeutic approach for patients with NAFLD.

Wnt3a regulates proliferation, apoptosis and function of pancreatic NIT-1 beta cells via activation of IRS2/PI3K signaling.

Wnt-signaling pathway is implicated in pancreatic development and functional regulation of mature beta-cells. Wnt3a/Wnt pathway activation expands islet cell mass in vitro by increasing proliferation and decreasing apoptosis of beta-cells, thereby enhancing its function. However, the signaling pathways that mediate these effects remain unknown. By using a clonal beta-cell line (NIT-1), we examined the role of IRS2/PI3K in the mediation of Wnt3a-stimulated beta-cell growth. Real-time PCR and Western blot were employed to investigate the activity of Wnt/ß-catenin and IRS2/PI3K signaling. Proliferation of NIT-1 cells was assessed by BrdU incorporation, and apoptosis was quantitatively determined by TUNEL and flow cytometry (FCM). Dkk1, an inhibitor of Wnt signaling, and wortmannin, an inhibitor of PI3K, were also used. Results showed that Wnt3a rapidly activated Wnt/ß-catenin signaling, promoted IRS2 expression and Akt phosphorylation in NIT-1 cells. These effects were completely abrogated by Dkk1 or partially eliminated by wortmannin. Wnt3a also promoted NIT-1 cell proliferation, inhibited cytokine-induced beta-cell apoptosis, and increased insulin secretion. Both of these effects were also eliminated by Dkk1 or wortmannin. Our results demonstrated that Wnt3a regulates proliferation, apoptosis and enhances function of pancreatic NIT-1 beta cells via activation of Wnt/ß-catenin signaling, involving crosstalk with IRS2/PI3K signaling, with the effect of Wnt signaling on beta-cells also being IRS2/PI3K/AKT dependent.

Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction.

The increasing incidence of type 2 diabetes mellitus is partially due to the rising obesity rates and the elevated levels of free fatty acids (FFAs). It is known that FFAs are putative mediators of beta-cell dysfunction, which is characterized with impaired glucose-stimulated insulin secretion and increased apoptosis, being defined as lipotoxicity. To date, many factors and their related signal pathways have been reported to be involved in FFA-induced beta-cell dysfunction. However, the entire blueprint is still not obtained. Some essential and newfound effectors, including the sterol regulatory element-binding protein (SREBP)-1c, farnesoid X receptor (FXR), forkhead box-containing protein O (FoxO) 1, ubiquitin C-terminal hydrolase L (UCHL) 1, N-myc downstream-regulated gene (NDRG) 2, perilipin family proteins, silent information regulator 2 protein 1 (Sirt1), pituitary adenylate cyclase-activating polypeptide (PACAP), and ghrelin are described in this review, which may help to further understand the molecular network for lipotoxicity.