Liraglutide improves insulin sensitivity in high fat diet induced diabetic mice through multiple pathways.

Glucagon like peptide-1 (GLP-1) promotes postprandial insulin secretion. Liraglutide, a full agonist of the GLP-1 receptor, reduces body weight, improve insulin sensitivity, and alleviate Non Alcoholic Fatty Liver Disease (NAFLD). However, the underlying mechanisms remain unclear. This study aims to explore the underlying mechanisms and cell signaling pathways involved in the anti-obesity and anti-inflammatory effects of liraglutide. Mice were fed a high fat high sucrose diet to induce diabetes, diabetic mice were divided into two groups and injected with liraglutide or vehicle for 14 days. Liraglutide treatment improved insulin sensitivity, accompanied with reduced expression of the phosphorylated Acetyl-CoA carboxylase-2 (ACC2) and upregulation of long chain acyl CoA dehydrogenase (LCAD) in insulin sensitive tissues. Furthermore, liraglutide induced adenosine monophosphate-activated protein kinase-α (AMPK-α) and Sirtuin-1(Sirt-1) protein expression in liver and perigonadal fat. Liraglutide induced elevation of fatty acid oxidation in these tissues may be mediated through the AMPK-Sirt-1 cell signaling pathway. In addition, liraglutide induced brown adipocyte differentiation in skeletal muscle, including induction of uncoupling protein-1 (UCP-1) and PR-domain-containing-16 (PRDM-16) protein in association with induction of SIRT-1. Importantly, liraglutide displayed anti-inflammation effect. Specifically, liraglutide led to a significant reduction in circulating interleukin-1 ß (IL-1 ß) and interleukin-6 (IL-6) as well as hepatic IL-1 ß and IL-6 content. The expression of inducible nitric oxide synthase (iNOS-1) and cyclooxygenase-2 (COX-2) in insulin sensitive tissues was also reduced following liraglutide treatment. In conclusion, liraglutide improves insulin sensitivity through multiple pathways resulting in reduction of inflammation, elevation of fatty acid oxidation, and induction of adaptive thermogenesis.

Berberine hydrochloride protects against cytokine-induced inflammation through multiple pathways in undifferentiated C2C12 myoblast cells.

Obesity is associated with skeletal muscle insulin resistance and the development of metabolic syndrome. Undifferentiated skeletal muscle cells are sensitive to oxidative stress. Berberine hydrochloride (BBR) improves insulin resistance and exhibits anti-inflammatory properties. However, the underlying mechanism and the cell signaling pathways involved remain largely elusive. We therefore investigated the anti-inflammatory effects of BBR and the signaling pathways using skeletal C2C12 myoblast cells. Undifferentiated C2C12 myoblast cells were treated with interleukin-1ß alone or in combination with tumor necrosis factor-α in the presence or absence of BBR. We found that BBR reduced the cytokine-induced expression of inducible nitric oxide synthase and stress-related kinases including p-38 mitogen-activated protein kinase, nuclear factor kappa B (NF-κB), and stress-activated protein kinases/Jun amino-terminal kinases (SAPK/JNK) in C2C12 myoblast cells. Furthermore, BBR reversed cytokine-mediated suppression of AMP-activated protein kinase (AMPKα), sirtuin-1 (SIRT-1), and PPAR-γ coactivator-1α (PGC-1α). In addition, cytokine-induced reduction of mitochondrial marker proteins and function were rescued after BBR treatment. Catalase, an antioxidant enzyme, was elevated after BBR treatment. Our results demonstrate that BBR ameliorates cytokine-induced inflammation. The anti-inflammatory effect of BBR in skeletal progenitor cells is mediated through pathways including activation of the AMPKα-SIRT-1-PGC-1α, inhibition of the mitogen-activated protein kinase 4 (MKK4)-SAPK/JNK-C-JUN, as well as protection of mitochondrial bioenergetics. BBR may be a potential medication for metabolic syndrome.

Diabetes and Associated Cardiovascular Complications in American Indians/Alaskan Natives: A Review of Risks and Prevention Strategies.

Diabetes mellitus (DM) is the seventh leading cause of death in the United States and the leading cause of death in the U.S. American Indian/Alaskan Natives (AI/ANs), who comprise only 2% of the total population. The AI/AN population has a high prevalence of DM in adults aged 20 years or older and is developing DM at a younger age than the general U.S. POPULATION: DM is a major risk factor for cardiovascular disease (CVD), and mortality from CVD is higher in AI/ANs than the general population, as is the prevalence of stroke and 1-year poststroke mortality for both genders when compared to non-Hispanic whites. A genome-wide scan found a number of chromosome linkages in the AI/AN population that suggest that genetic factors may contribute to their high risk of DM and CVD. Importantly, studies also suggest that in addition to race/ethnicity, cultural norms and historic conditions play important roles in the prevalence of DM and CVD in this population. Therefore, multiple factors should be taken into consideration when establishing prevention programs to decrease the prevalence of obesity, diabetes, and CVD incidence among adults and children in the AI/AN population. Prevention programs should focus on behavioral risk factors and lifestyle changes like encouraging smoking cessation, healthy diet, and increased physical activity while taking into consideration cultural, economic, and geographic factors.

Sleep duration and smoking are associated with coronary heart disease among US adults with type 2 diabetes: Gender differences.

AIMS: The associations of moderate alcohol consumption, sleep duration, and tobacco smoking with coronary heart disease (CHD) among patients with type 2 diabetes mellitus (T2D) are not clearly clarified. The aims of the study were to evaluate the associations of lifestyle factors, hypertension, obesity, depression and sleep duration with CHD development among patients with T2D, and particularly, to examine the gender differences in risk factors for CHD. METHODS: A total of 2335 T2D adults were selected from the 2012 National Health Interview Survey. Weighted univariate and multiple logistic regression analyses were used to estimate the odds ratios with 95% confidence intervals. RESULTS: The CHD prevalence among patients with T2D was 14.2% (18.1% and 10.4% for males and females, respectively), which increased with age (10.3% and 19.6% for age groups 18-64 and 65+, respectively). After adjusting for other factors, weighted logistic regression analyses showed that CHD among patients with T2D was significantly associated with being male, older age, past smoking, long sleep duration, hypertension, and high cholesterol level. Furthermore, the significant association of older age, past smoking, hypertension and high cholesterol level were observed particularly in males, while the association of long sleep duration with CHD was only observed in females. Hypertension was associated with CHD for both genders. CONCLUSIONS: Gender, age, past smoking, long sleep duration, hypertension and high cholesterol level were significantly associated with CHD among T2D patients; however, such associations differed by gender. Such gender disparities should be considered in the prevention and treatment of T2D.

Integrating Medical Simulation Into the Physician Assistant Physiology Curriculum.

PURPOSE: Medical simulation has recently been used in medical education, and evidence indicates that it is a valuable tool for teaching and evaluation. Very few studies have evaluated the integration of medical simulation in medical physiology education, particularly in PA programs. This study was designed to assess the value of integrating medical simulation into the PA physiology curriculum. METHODS: Seventy-five students from the PA program at Central Michigan University participated in this study. Mannequin-based simulation was used to simulate a patient with hemorrhagic shock and congestive heart failure to demonstrate the Frank-Starling force and cardiac function curve. Before and after the medical simulation, students completed a questionnaire as a self-assessment. A knowledge test was also delivered after the simulation. RESULTS: Our study demonstrated a significant improvement in student confidence in understanding congestive heart failure, hemorrhagic shock, and the Frank-Starling curve after the simulation. CONCLUSIONS: Medical simulation may be an effective way to enhance basic science learning experiences for students and an ideal supplement to traditional, lecture-based teaching in PA education.

A New Role for an Old Drug: Metformin Targets MicroRNAs in Treating Diabetes and Cancer.

MicroRNAs (miRNAs) are a family of short, noncoding, 19-23 base pair RNA molecules. Due to their unique role in gene regulation in various tissues, miRNAs play important roles in regulating insulin secretion, metabolic disease, and cancer biology. Emerging evidence demonstrates that miRNAs could also be novel diagnostic markers for a variety of disease states. Additionally, miRNAs have been found to function either as oncogenes, or tumor suppressor genes in cerian cancers. An increasing number of studies have been conducted investigating new drugs targeting miRNAs as a potential anticancer therapy. Metformin is the most widely prescribed medication for treating Type 2 diabetes (T2D). Recent clinical data suggests that metformin impacts the miRNA profile in T2D subjects. Most excitingly, studies have found that metformin is protective against cancer. The anticancer activity of metformin is mediated through a direct regulation of miRNAs, which further modulates several downstream genes in metabolic or preoncogenic pathways. These miRNAs are, therefore, prospective therapeutic targets for treating diabetes and cancer which is the topic of this review. Further study on the regulation of miRNAs by metformin could result in novel therapeutic strategies for recurrent or drug-esistant cancer, and as part of combinatorial approaches with conventional anticancer therapies.

MicroRNAs are key regulators of brown adipogenesis.

The recent discovery of microRNA, thousands of short, non-coding strands of RNA that regulate gene expressions on the transcriptional level throughout the body, raises the possibility of their roles as therapeutic targets in the treatment of a diverse range of diseases including diabetes, cancer, cardiovascular disease, and obesity. Specifically, their potential as therapeutic targets in the treatment of obesity has been highlighted. Brown adipose tissue containing a large number of mitochondria and expressing Ucp-1 is metabolically active through dissipating energy as heat in cold temperatures. Brown adipose, which was previously thought to be present only in neonatal and infants, has been recently unexpectedly identified in various anatomical regions of the adult human body. Furthermore, brown adipocytes have been shown to originate from skeletal and cardiovascular myoblast progenitor cells. Several identified microRNAs participate in the regulation of brown adipocyte differentiation through pathways involving the Prdm16 and C/ebp-ß program. These miRNAs are potential therapeutic targets in the induction of brown adipocyte lineage differentiation from myoblast and white adipose, through which the Ucp-1 expression is regulated to increase calorie expenditure and reduce body weight in obese individuals. This review focuses on the current understanding of miRNAs on the regulation of brown adipogenesis.