Resistin is a cysteine-rich cytokine, which has been indicated as a mediator of insulin resistance and inflammation. Previous studies demonstrated that lipoprotein lipase (LPL) was an important enzyme that could mediate lipid accumulation in macrophages. Additionally, the intracellular molecules phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT)/peroxisome proliferator-activated receptor (PPARγ) were supposed to be involved in the lipid accumulation process in cells. However, it remains unclear whether resistin was correlated with the dysregulation of lipid metabolism in macrophages. The present study investigated that resistin could up-regulate the expression of LPL and increase the contents of intracellular triglyceride (TG) and total cholesterol (TC) in RAW264.7 macrophages. In addition, intracellular molecules PI3K, AKT and PPARγ were significantly up-regulated and activated in resitin-stimulated RAW264.7 macrophages (P < 0.05). In contrast, the effects of resistin on RAW264.7 macrophages could be abrogated by specific inhibitors for LPL (LPL-siRNA) and PI3K/AKT signaling pathway (LY294002). All together, this study demonstrated that resistin could up-regulate the expression of LPL and induce lipid accumulation in RAW264.7 macrophages. More importantly, the PPARγ-dependent PI3K/AKT signaling pathway was relevant to the lipid accumulation process in resistin-stimulated macrophages.

IN BRIEF Rates of obesity and diabetes are growing, as are their costs. Because the two diseases share many key determinants, the paradigms for their treatment overlap. For both, optimal treatment involves a multidisciplinary team following the Chronic Care Model of health care delivery. Combined treatment programs that include 1) a low-calorie diet individualized to patients' preferences, 2) structured exercise that is also tailored to each patient, and 3) psychotherapy induce the largest weight changes in patients with diabetes. Although diet alone can achieve weight loss, exercise and cognitive behavioral therapy components can enhance the effects of dietary modification. A multidisciplinary team that includes a physician with expertise in pharmacotherapy, a nurse and/or nurse practitioner, a dietitian, an exercise physiologist, and a psychologist can provide a comprehensive weight loss program combining the most effective interventions from each discipline.

Previous studies have indicated that resistin, a type of adipokine, contributes to the development of insulin resistance and type 2 diabetes mellitus, and mediates inflammatory reactions. However, a specific receptor for resistin has not yet been identified. In this study, the relationship between resistin and nucleotide-binding oligomerization domain-like receptors, as well as resistin signal transduction, was examined through transfection, quantitative polymerase chain reaction, western blot analysis and ELISA. The mRNA expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), a key immune receptor related to insulin resistance, was significantly increased by resistin treatment at concentrations of 100, 150 and 200 ng/ml (P<0.05, P<0.01 and P<0.01, respectively). The mRNA expression of downstream signaling molecules in the NOD2 signaling pathway, receptor-interacting serine/threonine-protein kinase 2 (RIP2; P<0.01 at 6, 12 and 24 h) and inhibitor of NF-κB kinase subunit beta (P<0.01 at 3, 6, 12 and 24 h) were significantly increased by resistin treatment compared with the control. The mRNA expression of key proinflammatory cytokines, tumor necrosis factor α, IL (interleukin)-6 and IL-1β, were also significantly increased by resistin treatment compared with the control (P<0.01). NOD2 knockdown by small interfering RNA (siRNA) significantly decreased the expression of NOD2 and RIP2 (P<0.01), and there was no significant increase in the levels of cytokines, as compared with treatment with control siRNA. These findings indicate that the inflammatory reaction induced by resistin involves the NOD2-nuclear factor (NF)-κB signaling pathway. The inhibition of NF-κB significantly decreased the secretion of key inflammatory cytokines (P<0.01), suggesting that NF-κB signaling mechanisms are essential to the resistin-induced inflammatory response.

Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes.

We investigated the effect of chronic administration of fluoxetine "FLU" and imipramine "IMIP" on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS).

Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-α and IL-1ß). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters.

FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects.

Hypertriglyceridaemia (HTG) is a risk factor for cardiovascular disease (CVD) in type 2 diabetes and is caused by the interaction of genes and non-genetic factors, specifically poor glycaemic control and obesity. In spite of statin treatment, residual risk of CVD remains high in type 2 diabetes, and this may relate to HTG and atherogenic dyslipidemia. Treatment of HTG emphasises correcting secondary factors and adverse lifestyles, in particular, diet and exercise. Pharmacotherapy is also required in most type 2 diabetic patients. Statins are the first-line therapy to achieve recommended therapeutic targets of plasma low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol. Fibrates, ezetimibe and n-3 fatty acids are adjunctive treatment options for residual and persistent HTG. Evidence for the use of niacin has been challenged by non-significant CVD outcomes in two recent large clinical trials. Further investigation is required to clarify the use of incretin-based therapies for HTG in type 2 diabetes. Extreme HTG, with risk of pancreatitis, may require insulin infusion therapy or apheresis. New therapies targeting HTG in diabetes need to be tested in clinical endpoint trials. The purpose of this review is to examine the current evidence and provide practical guidance on the management of HTG in type 2 diabetes.

Dyslipidemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. The characteristic features of diabetic dyslipidemia are a high plasma triglyceride concentration, low HDL cholesterol concentration and increased concentration of small dense LDL-cholesterol particles. The lipid changes associated with diabetes mellitus are attributed to increased free fatty acid flux secondary to insulin resistance. The availability of multiple lipid-lowering drugs and supplements provides new opportunities for patients to achieve target lipid levels. However, the variety of therapeutic options poses a challenge in the prioritization of drug therapy. The prevalence of hypercholesterolemia is not increased in patients with diabetes mellitus, but mortality from coronary heart disease increases exponentially as a function of serum cholesterol levels, and lowering of cholesterol with statins reduces diabetic patients' relative cardiovascular risk. Although drug therapy for dyslipidemia must be individualized, most people with diabetes mellitus are candidates for statin therapy, and often need treatment with multiple agents to achieve therapeutic goals.

Most gene expression studies examining the effect of obesity and weight loss have been performed using adipose tissue. However, the liver also plays a central role in maintaining energy balance. We wanted to study the effects of a hypocaloric diet on overall hepatic gene expression and metabolic risk factors.

The study subjects were middle-aged, obese women. The diet intervention subjects (n=12) were on a hypocaloric, low-fat diet for 8 weeks with a daily energy intake of 5.0 MJ (1200 kcal), while the control subjects (n=19) maintained their weight. Liver biopsies were taken at the end of the diet period during a gallbladder operation. Hepatic gene expression was analyzed using microarrays by comparing the gene expression profiles from four subjects per group. A global decrease in gene expression was observed with 142 down-regulated genes and only one up-regulated gene in the diet intervention group. The diet resulted in a mean weight loss of 5% of body weight. Triglyceride and fasting insulin concentrations decreased significantly after the diet.

The global decrease in hepatic gene expression was unexpected but the results are interesting, since they included several genes not previously linked to weight reduction. However, since the comparison was made only after the weight reduction, other factors in addition to weight loss may also have been involved in the differences in gene expression between the groups. The decrease in triglyceride and fasting plasma insulin concentrations is in accordance with results from previous weight-loss studies.

The prevalence of diabetes worldwide is increasing rapidly in association with the increase in obesity. Complications are a major fear of patients with diabetes. Complications of diabetes affect many tissues and organs, causing retinopathy, nephropathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, stroke, and periodontal pathologies. Immunologic abnormalities are associated with type 1 and type 2 diabetes and diabetic complications. T cell abnormalities are believed to be the major cause of autoimmune disease in type 1 diabetes, leading to the destruction of pancreatic islets. In type 2 diabetes, inflammation and activation of monocytes are postulated to be important for enhancing insulin resistance and may contribute to the loss of insulin secretory function by islet cells. Many factors can enhance insulin resistance, including genetics, a sedentary lifestyle, obesity, and other conditions, such as chronic inflammation or infection. Increases in inflammation, such as activation of monocytes and increased levels of inflammatory markers, e.g., C-reactive protein, plasminogen activator inhibitor-1, and other cytokines, were reported in insulin-resistant states without diabetes. One possible mechanism is that abnormal levels of metabolites, such as lipids, fatty acids, and various cytokines from the adipose tissue, activate monocytes and increase the secretion of inflammatory cytokines, enhancing insulin resistance. According to this model, obesity activates monocytes and enhances insulin resistance, increasing the risk for type 2 diabetes. Abnormalities in innate immunity might also participate in the development of diabetic complications. In general, hyperglycemia is the main initiator of diabetic retinopathy, nephropathy, and neuropathy, and it participates in the development of diabetic cardiovascular diseases. Although the precise role of inflammation in the development of diabetic microvascular diseases is still unclear, it is likely that inflammation induced by diabetes and insulin resistance can accelerate atherosclerosis in patients with diabetes. Also, it was shown that conditions with an inflammatory basis, such as obesity and type 2 diabetes, can contribute to periodontal disease, suggesting that periodontal abnormalities may be partly influenced by inflammatory changes. Further research is required to confirm the role of inflammation and the onset of diabetes, microvascular diseases, and periodontal pathologies.

Conjugated linoleic acid (CLA) is a class of positional, geometric, conjugated dienoic isomers of linoleic acid. Dietary CLA supplementation has resulted in a dramatic decrease in body fat mass in mice. However, some but not all studies in mice and humans have found that CLA promoted insulin resistance, and there were conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-gamma (PPAR gamma) activation and expression. The objective of present study was to investigate the effect of CLA on insulin resistance and its molecular mechanisms. Fifty male Wistar rats were randomly designed to the control, high-fat and high-fat with CLA (0.75, 1.50, and 3.00 g in per 100 g diet) groups. The effect of CLA on insulin sensitivity and the mechanism of resisting diabetes by CLA were investigated by RT-PCR assay. The results showed that supplementation with CLA significantly reduced body weight gain and white fat pad weight in the rats, the levels of plasma free fatty acids (FFA), triglycerides (TGs), cholesterin (TC), leptin, insulin and blood glucose concentration in the obese rats of CLA group were also decreased compared to the rats in the high-fat group. Dietary CLA increased the mRNA expression of PPAR gamma, fatty acid binding proteins (aP2), fatty acid transporter protein (FATP), acyl-CoA synthetase (ACS) and adiponectin in the adipose tissues of obese rats. The results suggest that CLA may ameliorate insulin resistance by activating PPAR gamma, and increasing the expression of PPAR gamma target genes such as ap2, FATP, FAT, and adiponectin in the white adipose tissue.

Obesity is associated with a 3-or-more-fold increase in the risk of fatal and nonfatal myocardial infarction (1,2,3,4,5,6). The American Heart Association has reclassified obesity as a major, modifiable risk factor for coronary heart disease (7). The increased prevalence of premature coronary heart disease in obesity is attributed to multiple factors (8,9,10). A principal contributor to this serious morbidity is the alterations in plasma lipid and lipoprotein levels. The dyslipidemia of obesity is commonly manifested as high plasma triglyceride levels, low high-density lipoprotein cholesterol (HDLc), and normal low-density lipoprotein cholesterol (LDLc) with preponderance of small dense LDL particles (7,8,9,10). However, there is a considerable heterogeneity of plasma lipid profile in overweight and obese people. The precise cause of this heterogeneity is not entirely clear but has been partly attributed to the degree of visceral adiposity and insulin resistance. The emergence of glucose intolerance or a genetic predisposition to familial combined hyperlipidemia will further modify the plasma lipid phenotype in obese people (11,12,13,14,15).

The cause of obesity-related low HDLc in the absence of hypertriglyceridemia is not known.

A total of 32 subjects with a body mass index (BMI)(kg/m(2)) greater than 30 and normal serum triglycerides (<150 mg/dl) were identified.

People with low HDLc (n = 16) compared to those with normal HDLc (n = 16) had higher BMI (37.53 +/- 4.54 vs. 33.99 +/- 3.65 kg/m(2), p < 0.021), higher body fat weight (42.59 +/- 9.51 vs. 34.76 +/- 8.7 kg, p < 0.023), and higher insulin resistance index (3.75 +/- 2.51 vs. 1.95 +/- 1.10, p < 0.013). Seven subjects with low HDLc and none of those with normal HDLc, had elevated serum tumor necrosis factor alpha and/or interleukin-6 (p < 0.010).

Low HDLc levels can occur in obesity independently of elevated serum triglycerides and may be secondary to elevated serum levels of inflammatory cytokines.

A large difference in fat intake and pancreatic cancer incidence exists among populations worldwide. This study investigated the relation between fat consumption and pancreatic cancer risk at the population level.

Fat consumption data for nine periods (1964-1994) and age-standardized pancreatic cancer incidence data for five periods (1973-1997) in 35 countries were derived from the Food and Agriculture Organization and World Health Organization, respectively.

A significant positive correlation was found between animal fat consumption and pancreatic cancer incidence in all periods examined (r=0.40-0.74, p=0.021 to < 0.0001 in men and r=0.50-0.66, p=0.01 to 0.0001 in women). After adjustment for smoking and other confounders, animal fat consumption in all nine periods considered was still significantly and positively associated with pancreatic cancer incidence in the 1993 to 1997 period in both sexes. The stratified analysis showed that this association was significant only in countries with below median level of smoking (< 2273 cigarettes/adult/year). A similar but less pronounced effect was observed for total fat consumption.

The consumption of fat, especially animal fat, was associated with an increased risk of pancreatic cancer and this association was modified by levels of cigarette smoking.

The metabolic syndrome is a condition associated with obesity, insulin resistance, hypertension, dyslipidemia, hypercoagulability, and chronic inflammation, all of which increase the risk of cardiovascular disease (CVD). The Third National Cholesterol Education Program Adult Treatment Panel extensively discussed the metabolic syndrome because it is a major health issue in the United States due to the national epidemic of obesity. Statins cause significant CVD risk reduction in patients with the metabolic syndrome by alterations in lipid levels and possibly by decreasing inflammation. Because of the increased CVD risk associated with the metabolic syndrome and extensive clinical trial evidence documenting reduction of CVD risk with statin treatment, all patients with the metabolic syndrome should be evaluated as candidates for statin treatment as part of a multidisciplinary approach to reduce CVD risk.

Insulin induces transcription of the hepatic apolipoprotein AI (apo AI) gene by increasing Sp1 binding to the promoter. To determine the effect of fatty acids on this process, HepG2 cells cotransfected with the plasmid pAI.474.CAT containing the full-length apo AI promoter and the Sp1-expressing plasmid, pCMV-Sp1, were studied. Chloramphenicol acetyl transferase (CAT) activity (% acetylation) increased 1.98-fold in cells receiving the Sp1 expression construct relative to control cells (46.4% +/- 0.6% v 23.4% +/- 1.3%, P < .05). Treatment of cells with 3 saturated fatty acids, stearic, myristic, and palmitic acid, repressed the ability of exogenous Sp1 to induce apo AI reporter gene expression (15.2% +/- 1.7%, 22.5% +/- 0.3%, 22.9% +/- 0.1%, 23.5% +/- 0.8%, respectively, P < .05). Unsaturated fatty acids, oleic, linoleic, or linolenic acid had no effect on Sp1-mediated induction of the apo AI promoter. In the presence of the trans fatty acids, CAT activity in the Sp1-transfected cells was similar to control cells (16.7% +/- 3.3%, 19.3% +/- 0.5%, and 21.0% +/- 2.1% acetylation in cells exposed to elaidic acid, linolelaidic, or linolenelaidic acid, respectively). In cells treated with an equimolar mixture of oleic acid and stearic acid, apo AI promoter activity was suppressed in a manner similar to that observed in stearic acid-treated cells. Insulin (100 microU/mL) induced apo AI promoter activity 2.9-fold (22.4% +/- 1.7% v 7.8% +/- 2.4%, P < .05). However, in the presence of stearic acid, insulin was unable to induce apo AI promoter (6.3% +/- 1.6%). Stearic acid treatment did not alter Sp1-DNA binding as measured by gel shift analysis. Therefore, saturated fatty acids blunt Sp1 induction of apo AI promoter probably at a step beyond DNA binding.

Cardiovascular disease continues to be the leading cause of mortality in diabetes. One of the factors contributing to the increased risk is the high prevalence rate of low plasma concentrations of HDL cholesterol. Multiple potential mechanisms account for the cardioprotective effects of HDL and its main protein apolipoprotein (apo) A-I. The reduced plasma concentrations of HDL could be the result of increased fractional clearance of HDL and reduced expression of apo A-I. In animal models of diabetes and in cell cultures treated with high concentrations of glucose, apo A-I expression is reduced. In this review we will discuss the alterations in transcriptional control of apo A-I in diabetes. The role of select nutritional and hormonal alterations commonly found in diabetes will be reviewed. Specifically, we will review the literature on the effect of hyperglycemia, hypoinsulinemia, and ketoacidosis, as well as the role of various mediators of insulin resistance, such as fatty acids, cytokines, and prostanoids, on apo A-I promoter activity. Identifying the mechanisms that modulate apo A-I gene expression will aid in the new development of therapeutic agents that increase plasma apo A-I and HDL concentrations.

Obesity has now been identified as a chronic disease, a global epidemic (globesity) and a serious public health issue that leads to reduced life expectancy, an increased risk for many serious medical conditions and enormous healthcare costs. The prevalence of obesity and overweight in Italy in 2000 was respectively 9% and 33%, and has grown by 25% over the last five years. Even moderate weight loss can improve obesity-related morbidity and mortality. In November 1997, the US Food and Drug Administration approved sibutramine, a serotonin and noradrenaline reuptake inhibitor, for the treatment of pathological obesity and the management and maintenance of weight loss. In March 2002, sibutramine was temporarily withdrawn from the Italian market on the basis of 47 adverse event reports received between April and December 2001. However, a worldwide review of efficacy and safety data has shown that the overall risk/benefit profile of sibutramine remains favourable, with the rate of fatal reports involving patients receiving sibutramine being 200 times less than the obese women's mortality rate in the Nurses' Health Study. There is strong evidence supporting the usefulness of the correct use of sibutramine in the management of obesity.

Cloning of the insulin-like growth factor I (IGF-I) gene led to the development in 1987 of recombinant IGF-I available for clinical use. Trials were started targeting endocrine, metabolic and neurological disorders, and beneficial results have been demonstrated in IGF-I deficiency states caused by IGF-I gene deletion and growth hormone (GH) receptor deficiency, type 1 and type 2 diabetes mellitus, and severe insulin resistance syndromes. Results of equivocal benefit have also been reported in osteoporosis and amyotrophic lateral sclerosis. Recent encouraging data using the IGF-I-IGF-binding protein 3 (IGFBP-3) complex in diabetes mellitus suggest that this preparation may eventually replace recombinant free IGF-I. The lack of an established therapeutic indication for IGF-I has resulted in its supplies being severely limited. It will probably be decided during the next decade whether use of IGF-I or the IGF-I-IGFBP-3 complex becomes firmly established as an accepted endocrine therapy.