Insulin-sensitive Organs Research Articles

Ectopic fat and cardiovascular disease: What is the link?

Aim of this paper is to review the recent literature on the relationship between ectopic fat accumulation and cardiovascular disease. Data synthesis Ectopic fat is an important predictor of metabolic (in particular insulin resistance) and cardiovascular disease, carrying more risk than general fat accumulation. Recent studies have shown a link between ectopic fat accumulation, as cardiac (epicardial or intra-myocardial fat) and/or visceral and/or hepatic fat, and development of atherosclerosis, coronary heart disease and hypertension. Conclusions Ectopic fat accumulation is not only a marker of cardiometabolic disease, since through the release of adipocitokines, lipotoxic and glucotoxic agents, participates in the crosstalk with insulin-sensitive organs leading to metabolic, cardiac and vascular dysfunctions.

Insulin-mediated Regulation of Decidual Protein Induced by Progesterone (DEPP) in Adipose Tissue and Liver

We analyzed the profile of the genes expressed in human adipose tissue and identified the fat-derived molecules, adiponectin and aquaporin 7, which modulate glucose and lipid metabolism. The same Bodymap analysis revealed abundant expression of the decidual protein induced by progesterone (DEPP) in the white adipose tissue. Northern blot analysis confirmed that human DEPP mRNA was highly expressed in white adipose tissue. Mouse DEPP mRNA was detected in heart, lung, skeletal muscle, and white adipose tissue under feeding state. In contrast, under fasting state, mouse DEPP mRNA was enhanced in lung, skeletal muscle, and white adipose tissue and it appeared also in the liver and kidney, suggesting up regulation of DEPP by fasting. Because fasting-induced DEPP expression was observed in insulin-sensitive organs, we investigated the regulation of DEPP in white adipose tissue and liver. During adipogenesis of mouse 3T3-L1 cells, DEPP mRNA increased in a differentiation-dependent manner similar to adiponectin and aquaporin 7. Treatment of cultured 3T3-L1 mature adipocytes, rat H4IIE, and human HepG2 hepatoma cells with insulin significantly decreased DEPP mRNA levels in dose- and time-dependent manners. IN VIVO experiments showed significant decrease of hepatic and adipose DEPP mRNA levels in refed mice, compared to fasted animals, and also showed significant increase in DEPP mRNA in streptozotocin-induced insulin-deficient diabetic mice. These results indicate that DEPP is a novel insulin-regulatory molecule expressed abundantly in insulin-sensitive tissues including white adipose tissue and liver.

Interleukin-1 beta targeted therapy for type 2 diabetes

Since having been cloned in 1984, IL-1β has been the subject of over 22,000 citations in Pubmed, among them over 800 reviews. This is because of its numerous effects. IL-1β is a regulator of the body's inflammatory response and is produced after infection, injury, and antigenic challenge. It plays a role in various diseases, including autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases and type 1 diabetes, as well as in diseases associated with metabolic syndrome such as atherosclerosis, chronic heart failure and type 2 diabetes. Macrophage are the primary source of IL-1, but epidermal, epithelial, lymphoid and vascular tissues also synthesize IL-1. IL-1β production and secretion have also been reported from pancreatic islets. Insulin-producing β-cells within pancreatic islets are specifically prone to IL-β-induced destruction and loss of function. Macrophage-derived IL-1β production in insulin-sensitive organs, leads to progression of inflammation and induction of insulin resistance in obesity. We summarize the mechanisms involved in inflammation and specifically the IL-1β signals that lead to the progression of insulin resistance and diabetes. We highlight recent clinical studies and experiments in animals and isolated islets using IL-1β as a potential target for the therapy of type 2 diabetes.

SIRT1 and insulin resistance

Sirtuin 1 (SIRT1), the mammalian homolog of SIR2, was originally identified as a NAD-dependent histone deacetylase, the activity of which is closely associated with lifespan under calorie restriction. Growing evidence suggests that SIRT1 regulates glucose or lipid metabolism through its deacetylase activity for over two dozen known substrates, and has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. SIRT1 stimulates a glucose-dependent insulin secretion from pancreatic beta cells, and directly stimulates insulin signaling pathways in insulin-sensitive organs. Furthermore, SIRT1 regulates adiponectin secretion, inflammatory responses, gluconeogenesis, and levels of reactive oxygen species, which together contribute to the development of insulin resistance. Moreover, overexpression of SIRT1 and several SIRT1 activators has beneficial effects on glucose homeostasis and insulin sensitivity in obese mice models. These findings suggest that SIRT1 might be a new therapeutic target for the prevention of disease related to insulin resistance, such as metabolic syndrome and diabetes mellitus, although direct evidence from clinical studies in humans is needed to prove this possibility. In this Review, we discuss the potential role and therapeutic promise of SIRT1 in insulin resistance on the basis of the latest experimental studies.

Obesity Upregulates Genes Involved in Oxidative Phosphorylation in Livers of Diabetic Patients

Obesity is a major cause of insulin resistance and contributes to the development of type 2 diabetes. The altered expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) has been regarded as a key change in insulin-sensitive organs of patients with type 2 diabetes. This study explores possible molecular signatures of obesity and examines the clinical significance of OXPHOS gene expression in the livers of patients with type 2 diabetes. We analyzed gene expression in the livers of 21 patients with type 2 diabetes (10 obese and 11 nonobese patients; age, 53.0 +/- 2.1 years; BMI, 24.4 +/- 0.9 kg/m(2); fasting plasma glucose, 143.0 +/- 10.6 mg/dl) using a DNA chip. We screened 535 human pathways and extracted those metabolic pathways significantly altered by obesity. Genes involved in the OXPHOS pathway, together with glucose and lipid metabolism pathways, were coordinately upregulated in the liver in association with obesity. The mean centroid of OXPHOS gene expression was significantly correlated with insulin resistance indices and the hepatic expression of genes involved in gluconeogenesis, reactive oxygen species (ROS) generation, and transcriptional factors and nuclear co-activators associated with energy homeostasis. In conclusion, obesity may affect the pathophysiology of type 2 diabetes by upregulating genes involved in OXPHOS in association with insulin resistance markers and the expression of genes involved in hepatic gluconeogenesis and ROS generation.

Mitochondrial dysfunction and insulin resistance: a matter of lifestyle?

Insulin resistance reflects a pathological state defined as blunted responses of insulin-sensitive organs, such as the liver, adipose tissue or skeletal muscle, to the usual effects of insulin. Insulin resistance is frequently present in metabolic disorders, may even cause a compensatory increase of insulin secretion, and is typically marked by hyperinsulinemia. Since insulin resistance is thought to play a central role in the pathogenesis of many metabolic disorders [1], several researchers have focused their efforts in trying to identify the primary mechanism(s) underlying this defect.

MicroRNAs: A new class of regulatory genes affecting metabolism

MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression by binding to target mRNAs, which leads to reduced protein synthesis and sometimes decreased steady-state mRNA levels. Although hundreds of miRNAs have been identified, much less is known about their biological function. Several studies have provided evidence that miRNAs affect pathways that are fundamental for metabolic control in higher organisms such as adipocyte and skeletal muscle differentiation. Furthermore, some miRNAs have been implicated in lipid, amino acid, and glucose homeostasis. These studies open the possibility that miRNAs may contribute to common metabolic diseases and point to novel therapeutic opportunities based on targeting of miRNAs.

Pathogenesis and Clinical Features of Obesity and Insulin Resistance

The etiology of obesity is not simple as multiple genetic and environmental factors, first of which is an increasingly sedentary lifestyle, play interacting roles. It is well recognized that persons with obesity carry a high risk of insulin resistance and its metabolic complications, such as impaired glucose tolerance, type 2 diabetes, hyperlipidemia and hypertension, and a significantly increased risk of atherothrombotic cardiovascular disease. Recent data have shown that not only generalized obesity, but rather ectopic fat accumulation, is associated with the risk of comorbidity. This article focuses on the clinical evidence related to the impact of regional adiposity on insulin resistance, with particular attention to central obesity, including fat accumulation in insulin sensitive organs, such as liver, muscle and heart, and the recent interest in adipokines. Keywords: Visceral fat, liver fat, epicardial fat, obesity, insulin resistance

The nicotinic acid receptor–a new mechanism for an old drug

Non-esterified fatty acids in plasma originate from adipose tissue. Delivery of fatty acids to the liver provides the substrate for VLDL triglycerides. Insulin-sensitive organs, overburdened by high concentrations of non-esterified fatty acids, may develop resistance to insulin action. In addition, insulin secretion from pancreatic beta-cells may be impaired by long-standing elevation of concentrations of non-esterified fatty acid in plasma. Normally, such concentrations fluctuate over the day depending on the transient suppression of lipolysis from adipose tissue by insulin released after meals. Diurnal concentrations of non-esterified fatty acid are often elevated in obesity, in particular in male-pattern upper-body fat accumulation. Nicotinic acid is the only drug that primarily lowers concentrations of non-esterified fatty acids and thereby lowers VLDL triglycerides. Nicotinic acid, or its analogues, seems to alleviate insulin resistance in the short-term whereas, paradoxically, the long-term effect is often the opposite. Suppression of lipolysis by nicotinic acid gives rise to a prominent rebound and the degree to which this occurs might explain this paradox. The exact cellular mechanism by which nicotinic acid exerts its antilipolytic effects has not been known until the recent discovery of a distinct G-protein coupled receptor. Nicotinic acid is a high affinity ligand, but the endogenous ligand is still unknown. Recently, Tina Rubic and colleagues (Biochem Pharmacol 2004; 67: 411-19) proposed a mechanism in which nicotinic acid stimulates cholesterol mobilisation from macrophages, thereby providing a potential link between regression of atherosclerosis and use of nicotinic acid. Research on signalling through the nicotinic acid receptor might give rise to novel and more effective methods to interfere with fatty-acid metabolism, with insulin resistance, hyperlipidaemia, and atherosclerosis as target diseases.