Ectopic Fat Accumulation In Liver Research Articles

Presence of Liver Steatosis Is Associated With Greater Diabetes Remission After Gastric Bypass Surgery.

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and β-cell dysfunction. Ectopic fat accumulation in liver and muscle causes IR. Since bariatric and metabolic surgery significantly improves fatty liver disease, we hypothesized that coexistence of liver steatosis (i.e., when hepatic IR contributes in T2DM) would be associated with greater diabetes improvement after surgery. A total of 519 patients with T2DM who underwent Roux-en-Y gastric bypass and simultaneous liver biopsy and had a minimum 5-year follow-up were analyzed to assess the independent association between biopsy-proven liver steatosis and postoperative long-term diabetes remission (glycated hemoglobin <6.5% [48 mmol/mol] off medications). Of the 407 patients with biopsy-proven liver steatosis, long-term diabetes remission was achieved in 211 (52%) patients compared with remission in 44 out of 112 (39%) patients without steatosis (P = 0.027). In multivariable analysis, presence of liver steatosis was an independent predictor of long-term diabetes remission (odds ratio 1.96 [95% CI 1.04-3.72]; P = 0.038). Hepatocyte ballooning, lobular inflammation, or fibrosis at baseline did not predict diabetes remission. This study, for the first time, suggests that in patients with T2DM who are considering bariatric and metabolic surgery, coexistence of liver steatosis is associated with better long-term glycemic outcomes. Furthermore, our data suggest that there are distinct variants of T2DM in which metabolic responses to surgical weight loss are different. A subgroup of patients whose T2DM is characterized by the presence of hepatic steatosis (presumably associated with worse IR) experience better postoperative metabolic outcomes.

Adipose tissue morphology, imaging and metabolomics predicting cardiometabolic risk and family history of type 2 diabetes in non-obese men

We evaluated the importance of body composition, amount of subcutaneous and visceral fat, liver and heart ectopic fat, adipose tissue distribution and cell size as predictors of cardio-metabolic risk in 53 non-obese male individuals. Known family history of type 2 diabetes was identified in 25 individuals. The participants also underwent extensive phenotyping together with measuring different biomarkers and non-targeted serum metabolomics. We used ensemble learning and other machine learning approaches to identify predictors with considerable relative importance and their intricate interactions. Visceral fat and age were strong individual predictors of ectopic fat accumulation in liver and heart along with markers of lipid oxidation and reduced glucose tolerance. Subcutaneous adipose cell size was the strongest individual predictor of whole-body insulin sensitivity and also a marker of visceral and ectopic fat accumulation. The metabolite 3-MOB along with related branched-chain amino acids demonstrated strong predictability for family history of type 2 diabetes.

Adipocyte differentiation impairment as well as lipid metabolism and transport problems – major causes of genetic lipodystrophies

Lipodystrophies are heterogenic group of adipose tissue disorders with its general or partial atrophy. In case of congenital lipodystrophies disturbances of adipogenesis or/and alterations of adipocyte differentiation often occur leading to thermogenic adipocytes formation. Basic adipocyte functions can be perturbed, including improper synthesis of triacylglycerols and phospholipids of lipid droplet, but also impaired fatty acids release and intracellular lipid traffic. Lipodystrophy can result from weakening of adipose tissue structure, but also from improper function of both cytoskeleton and nuclear lamina leading to cell dysfunction. Lack of adipose tissue leads to a) increased plasma triacylglycerols level and ectopic fat accumulation in other tissues; b) total plasma cholesterol increase; c) plasma HDL-cholesterol decrease. Ectopic fat accumulation in liver can cause fatty liver and with time can lead to hepatomegaly and liver cirrhosis. Dysfunctions are proportional to the extent of fat tissue loss with generalized lipodystrophies patients developing complications at early ages. Diabetes and insulin resistance are common comorbidities. Improvement of diagnostic methods of medical genetics allows precise determination of their genotypes and correct diagnosis of patients suffering from lipodystrophy. For that reason number of described cases increased in recent years, also in Poland. New lipodystrophy types were described. Therefore there is a need to bring lipodystrophy syndromes for the attention of primary care physicians, pediatricians and endocrinologists.

Absence of Uncoupling Protein-3 at Thermoneutrality Impacts Lipid Handling and Energy Homeostasis in Mice.

The role of uncoupling protein-3 (UCP3) in energy and lipid metabolism was investigated. Male wild-type (WT) and UCP3-null (KO) mice that were housed at thermoneutrality (30 °C) were used as the animal model. In KO mice, the ability of skeletal muscle mitochondria to oxidize fatty acids (but not pyruvate or succinate) was reduced. At whole animal level, adult KO mice presented blunted resting metabolic rates, energy expenditure, food intake, and the use of lipids as metabolic substrates. When WT and KO mice were fed with a standard/low-fat diet for 80 days, since weaning, they showed similar weight gain and body composition. Interestingly, KO mice showed lower fat accumulation in visceral adipose tissue and higher ectopic fat accumulation in liver and skeletal muscle. When fed with a high-fat diet for 80 days, since weaning, KO mice showed enhanced energy efficiency and an increased lipid gain (thus leading to a change in body composition between the two genotypes). We conclude that UCP3 plays a role in energy and lipid homeostasis and in preserving lean tissues by lipotoxicity, in mice that were housed at thermoneutrality.

Adipocytedifferentiationimpairment as well as lipid metabolism and trasportproblems – major causes of geneticlipodystrophies

Lipodystrophies are heterogenic group of adipose tissue disorders with its general or partial atrophy. In case of congenital lipodystrophies disturbances of adipogenesis or/and alterations of adipocyte differentiation often occur leading to thermogenic adipocytes formation. Basic adipocyte functions can be perturbed, including improper synthesis of triacylglycerols and phospholipids of lipid droplet, but also impaired fatty acids release and intracellular lipid traffic. Lipodystrophy can result from weakening of adipose tissue structure, but also from improper function of both cytoskeleton and nuclear lamina leading to cell dysfunction. Lack of adipose tissue leads to a) increased plasma triacylglycerols level and ectopic fat accumulation in other tissues; b) total plasma cholesterol increase; c) plasma HDL-cholesterol decrease. Ectopic fat accumulation in liver can cause fatty liver and with time can lead to hepatomegaly and liver cirrhosis. Dysfunctionsare proportional to the extent of fat tissue loss with generalized lipodystrophies patients developing complications at early ages. Diabetes and insulin resistance are common comorbidities. Improvement of diagnostic methods of medical genetics allows precise determination of their genotypes and correct diagnosis of patients suffering from lipodystrophy. For that reason number of described cases increased in recent years, also in Poland. New lipodystrophy types were described. Therefore there is a need to bring lipodystrophy syndromes for the attention of primary care physicians, pediatricians and endocrinologists.

1H-MRS measured ectopic fat in liver and muscle is associated with the metabolic syndrome in Danish girls but not in boys with overweight and obesity.

SummaryBackgroundThe metabolic syndrome (MetS) is a complication to overweight and obesity, which can be observed already in childhood. Ectopic lipid accumulation in muscle and liver has been shown to associate with the development of insulin resistance and dyslipidemia. Thus, the interaction between MetS and ectopic fat may offer clinical relevance.ObjectivesTo investigate the prevalence of MetS, or components hereof, and ectopic fat accumulation in liver and skeletal muscle tissue in children, as well as interactions between these.MethodsTwo‐hundred‐and‐sixteen children and adolescents (95 boys) with overweight/obesity were investigated, as well as 47 controls (22 boys) with normal weight. The assessments included anthropometry, fasting blood biochemistry and blood pressure measurements. Liver and muscle lipid contents were assessed by proton magnetic resonance spectroscopy.ResultsWe observed an odds ratio in girls with overweight/obesity of 12.2 (95% confidence interval: [3.8; 49.0]) for exhibiting MetS when hepatic steatosis was present, whereas no association was observed in boys with overweight/obesity (odds ratio 0.7 [0.2; 2.7]). The odds ratio of exhibiting MetS in the presence of muscular steatosis was 3.5 [1.4; 9.5] in girls with overweight/obesity and 1.0 [0.2; 5.6] in boys with overweight/obesity. Similar results were seen for girls with overweight/obesity exhibiting concurrent hepatic and muscular steatoses.ConclusionHepatic and muscular steatoses were associated with MetS among girls, but not among boys with overweight/obesity.

Genetic Variation in Renal Expression of Folate Receptor 1 (Folr1) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome.

Metabolism of homocysteine and other sulfur amino acids is closely associated with metabolism of folates. In this study, we analyzed the possible role of folates and sulfur amino acids in the development of features of the metabolic syndrome in the BXH/HXB recombinant inbred strains derived from the spontaneously hypertensive rat (SHR) and Brown Norway progenitors. We mapped a quantitative trait locus for cysteine concentrations to a region of chromosome 1 that contains a cis-acting expression quantitative trait locus regulating mRNA levels of folate receptor 1 (Folr1) in the kidney. Sequence analysis revealed a deletion variant in the Folr1 promoter region of the SHR. Transfection studies demonstrated that the SHR-promoter region of Folr1 is less effective in driving luciferase reporter gene expression than the Brown Norway promoter region of Folr1. Results in the SHR.BN-chr.1 congenic strain confirmed that the SHR variant in Folr1 cosegregates with markedly reduced renal expression of Folr1 and renal folate reabsorption, decreased serum levels of folate, increased serum levels of cysteine and homocysteine, increased adiposity, ectopic fat accumulation in liver and muscle, reduced muscle insulin sensitivity, and increased blood pressure. Transgenic rescue experiments performed by expressing a Folr1 transgene in the SHR ameliorated most of the metabolic disturbances. These findings are consistent with the hypothesis that inherited variation in the expression of Folr1 in the kidney influences the development of the metabolic syndrome and constitutes a previously unrecognized genetic mechanism that may contribute to increased risk for diabetes mellitus and cardiovascular disease.

Fumaric acid esters can block pro-inflammatory actions of human CRP and ameliorate metabolic disturbances in transgenic spontaneously hypertensive rats.

Inflammation and oxidative stress have been implicated in the pathogenesis of metabolic disturbances. Esters of fumaric acid, mainly dimethyl fumarate, exhibit immunomodulatory, anti-inflammatory, and anti-oxidative effects. In the current study, we tested the hypothesis that fumaric acid ester (FAE) treatment of an animal model of inflammation and metabolic syndrome, the spontaneously hypertensive rat transgenically expressing human C-reactive protein (SHR-CRP), will ameliorate inflammation, oxidative stress, and metabolic disturbances. We studied the effects of FAE treatment by administering Fumaderm, 10 mg/kg body weight for 4 weeks, to male SHR-CRP. Untreated male SHR-CRP rats were used as controls. All rats were fed a high sucrose diet. Compared to untreated controls, rats treated with FAE showed significantly lower levels of endogenous CRP but not transgenic human CRP, and amelioration of inflammation (reduced levels of serum IL6 and TNFα) and oxidative stress (reduced levels of lipoperoxidation products in liver, heart, kidney, and plasma). FAE treatment was also associated with lower visceral fat weight and less ectopic fat accumulation in liver and muscle, greater levels of lipolysis, and greater incorporation of glucose into adipose tissue lipids. Analysis of gene expression profiles in the liver with Affymetrix arrays revealed that FAE treatment was associated with differential expression of genes in pathways that involve the regulation of inflammation and oxidative stress. These findings suggest potentially important anti-inflammatory, anti-oxidative, and metabolic effects of FAE in a model of inflammation and metabolic disturbances induced by human CRP.

Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet.

We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and β-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 β-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet.

Omega-3 Fatty Acids, Hepatic Lipid Metabolism, and Nonalcoholic Fatty Liver Disease

Long-chain omega-3 fatty acids belong to a family of polyunsaturated fatty acids that are known to have important beneficial effects on metabolism and inflammation. Such effects may confer a benefit in specific chronic noncommunicable diseases that are becoming very prevalent in Westernized societies [e.g., nonalcoholic fatty liver disease (NAFLD)]. Typically, with a Westernized diet, long-chain omega-6 fatty acid consumption is markedly greater than omega-3 fatty acid consumption. The potential consequences of an alteration in the ratio of omega-6 to omega-3 fatty acid consumption are increased production of proinflammatory arachidonic acid-derived eicosanoids and impaired regulation of hepatic and adipose function, predisposing to NAFLD. NAFLD represents a spectrum of liver fat-related conditions that originates with ectopic fat accumulation in liver (hepatic steatosis) and progresses, with the development of hepatic inflammation and fibrosis, to nonalcoholic steatohepatitis (NASH). If the adipose tissue is inflamed with widespread macrophage infiltration, the production of adipokines may act to exacerbate liver inflammation and NASH. Omega-3 fatty acid treatment may have beneficial effects in regulating hepatic lipid metabolism, adipose tissue function, and inflammation. Recent studies testing the effects of omega-3 fatty acids in NAFLD are showing promise and suggesting that these fatty acids may be useful in the treatment of NAFLD. To date, further research is needed in NAFLD to (a) establish the dose of long-chain omega-3 fatty acids as a treatment, (b) determine the duration of therapy, and (c) test whether there is benefit on the different component features of NAFLD (hepatic fat, inflammation, and fibrosis).

A Palaeolithic‐type diet causes strong tissue‐specific effects on ectopic fat deposition in obese postmenopausal women

Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids (MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women. Ten healthy, nonsmoking postmenopausal women with a body mass index (BMI) >27 (28-35) kg m(-2) were included in the study. Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid (IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy ((1) H-MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment (HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique. Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean -7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered. A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.

Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high‐fat diet likely by promoting insulin signaling in insulin‐target tissues

This study investigated the effect of chronic leucine supplementation on insulin sensitivity and the associated mechanisms in rats on high-fat diet (HFD). Male Sprague-Dawley rats were fed either normal chow diet or HFD supplemented with 0, 1.5, 3.0, and 4.5% leucine for 24weeks. We found that chronic leucine supplementation increased insulin sensitivity together with increased body weight in rats on HFD, but had no effect on insulin sensitivity in rats on normal chow diet. The increased insulin sensitivity by leucine supplementation was not associated with altered ectopic fat accumulation in liver and muscle, plasma levels of lipids and cytokines, but is associated with reduced oxidative stress and improved insulin signaling. Chronic leucine supplementation did not enhance insulin receptor substract-1 (IRS-1) phosphorylation on serine 302, but elevated basal IRS-1 phosphorylation on tyrosine 632 and improved insulin-stimulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR) phosphorylation in liver, skeletal muscle, and adipose tissue of rats on HFD rats, indicating leucine supplementation prevented HFD-induced insulin resistance in insulin-target tissues. Chronic leucine supplementation can increase insulin sensitivity and body weight likely by reducing oxidative stress and improving insulin signaling pathway in rats on HFD.

Folate Deficiency Is Associated With Oxidative Stress, Increased Blood Pressure, and Insulin Resistance in Spontaneously Hypertensive Rats

The role of folate deficiency and associated hyperhomocysteinemia in the pathogenesis of metabolic syndrome is not fully established. In the current study, we analyzed the role of folate deficiency in pathogenesis of the metabolic syndrome in the spontaneously hypertensive rat (SHR). Metabolic and hemodynamic traits were assessed in SHR/Ola rats fed either folate-deficient or control diet for 4 weeks starting at the age of 3 months. Compared to SHRs fed a folate-replete diet, SHRs fed a folate-deficient diet showed significantly reduced serum folate (104 ± 5 vs. 11 ± 1 nmol/L, P < 0.0005) and urinary folate excretion (4.3 ± 0.6 vs. 1.2 ± 0.1 nmol/16 h, P < 0.0005) together with a near 3-fold increase in plasma total homocysteine concentration (4.5 ± 0.1 vs 13.1 ± 0.7 μmol/L, P < 0.0005), ectopic fat accumulation in liver, and impaired glucose tolerance. Folate deficiency also increased systolic blood pressure by approximately 15 mm Hg (P < 0.01). In addition, the low-folate diet was accompanied by significantly reduced activity of antioxidant enzymes and increased concentrations of lipoperoxidation products in liver, renal cortex, and heart. These findings demonstrate that the SHR model is susceptible to the adverse metabolic and hemodynamic effects of low dietary intake of folate. The results are consistent with the hypothesis that folate deficiency can promote oxidative stress and multiple features of the metabolic syndrome that are associated with increased risk for diabetes and cardiovascular disease.

Predictors of Ectopic Fat Accumulation in Liver and Pancreas in Obese Men and Women

The aim of the present study was to determine the relationship between body fat distribution, adipocytokines, inflammatory markers, fat intake and ectopic fat content of liver and pancreas in obese men and women. A total of 12 lean subjects (mean age 47.25 ± 14.88 years and mean BMI 22.85 ± 2), 38 obese subjects (18 men and 20 women) with mean age 49.1 ± 13.0 years and mean BMI 34.96 ± 4.21 kg/m2 were studied. weight, height, BMI, waist circumference, as well as glucose, insulin, HOMA (homeostasis model assessment of insulin resistance), cholesterol, triglycerides, high-density lipoprotein cholesterol, high sensitivity C-reactive protein, daily energy intake, leptin, and adiponectin. Magnetic resonance was used to evaluate visceral, subcutaneous adipose tissue (SCAT) as well as liver and pancreas lipid content using in-phase and out-of-phase magnetic resonance imaging (MRI) sequence. Obese subjects had significantly higher weight, waist circumference, SCAT, deep SCAT, visceral adipose tissue (VAT), liver and pancreatic lipid content than lean subjects. Obese women had significantly lower VAT, liver and pancreas lipid content regardless of same BMI. In multiple regression analyses, the variance of liver lipid content explained by gender and VAT was 46%. When HOMA was added into a multiple regression, a small increase in the proportion of variance explained was observed. A 59.2% of the variance of pancreas lipid content was explained by gender and VAT. In conclusion, obese men show higher VAT and ectopic fat deposition in liver and pancreas than obese women despite same BMI. Independent of overall adiposity, insulin resistance, adiponectin and fat intake, VAT, measured with MRI, is the main predictor of ectopic fat deposition in both liver and pancreas.

The metabolic syndrome: what’s in a name?

Metabolic syndrome refers to a clustering of established (i.e. ‘traditional’) and emerging (i.e. ‘nontraditional’) cardiovascular disease (CVD) risk factors within a single individual [Matfin, 2009; Grundy, 2007; Fonseca, 2000]. Both the established risk factors, such as obesity, diabetes, dyslipidemia, and hypertension, and other ‘non-traditional’ risk factors are closely related to central obesity (especially intra-abdominal adiposity, which is also known as visceral obesity) [Matfin, 2009; Grundy, 2007; Lawlor et al. 2006; Fonseca, 2000]. The emerging risk factors include dysfunction of inflammation, coagulation, platelets, fibrinolysis, lipoproteins, endothe-lium, and miscellaneous biological processes [Fonseca, 2000]. Individuals may develop these factors in different orders, at different severities, and at different ages [Lawlor et al. 2006]. The underlying pathophysiology of the metabolic syndrome is considered to be related to central obesity and insulin resistance [Matfin, 2009; Grundy, 2007; Reaven, 2006]. Although the exact cause of the metabolic syndrome is not known, the association with obesity is very compelling. Adipocytes are the source of a number of important factors involved in a wide range of processes related to the features of the metabolic syndrome, including glucose and lipid metabolism, inflammation, and thrombosis (e.g. nonesterified fatty acids [NEFAs], adiponectin, leptin, visfatin, and plasminogen activator inhibitor type 1 [PAI-1]) [Iozzo, 2009; Kershaw and Flier, 2004]. With obesity, the outputs of all of these products are higher except for adiponectin, which is abnormally low. Excess release of NEFAs predisposes to ectopic fat accumulation in liver, muscle, and visceral adipose tissue stores and can result in abnormal function (termed ‘lipotoxicity’), including insulin resistance. Adipocyte hypertrophy (large adipocytes are more insulin resistant than smaller ones and secrete more pro-inflammatory adipocytokines) [O'Connell et al. 2010], visceral adiposity, and ectopic fat accumulation (this combination has been termed ‘adiposopathy’ or ‘sick fat’ by Bays in the US [Bays, 2009]) may result in the adverse metabolic and immune consequences that contribute to major CVD risk factors (e.g. glucose intolerance, high blood pressure [BP], and dyslipidemia). Insulin resistance is also considered an important factor in the etiology of this syndrome [Grundy, 2007; Lawlor et al. 2006; Reaven, 2006, 1988]. Insulin resistance can be defined in several ways, but is essentially an impaired biological response to insulin actions in the insulin-responsive tissues (i.e. liver, fat, and skeletal muscle) [Reaven, 2006]. However, despite the potential utility of having all of the CVD risk factors under an umbrella diagnosis of the metabolic syndrome, debate continues about its very existence [Cameron et al. 2009; Preiss and Sattar, 2009; Ferrannini, 2007; Pratley, 2007; Alberti and Zimmet, 2006; Kahn et al. 2005]. This debate is (in part) related to lack of a universally accepted definition of this state, but also to doubts regarding the need for these disparate CVD risk determinants to be ‘lumped’ together under one ‘artificial’ diagnostic heading. Is the utility of the metabolic syndrome simply related to its value as an aide-memoire for physicians to consider other CVD risk factors when confronted with a patient with one or more of these factors? Despite the controversies regarding the metabolic syndrome, this subject remains one of the most discussed and written about by both the lay public and healthcare professionals alike. For example, the term ‘metabolic syndrome’ results in almost 3 million hits on Google (this does not include all of the different permutations such as ‘therapy’, ‘criteria’, etc.) and about 30,000 results on PubMed (accessed 24 April 2010). In addition, the component risk factors include some of the most common and serious public health challenges facing both the developed and developing world today [Hossain et al. 2007]. With improvement in the economic situation in developing countries, increasing prevalence of obesity and the metabolic syndrome is seen in adults and particularly in children. The main causes are increasing urbanization, nutrition transition, and reduced physical activity [Misra and Khurana, 2008]. According to recent worldwide estimates, 1.7 billion people are classified as either overweight or obese, more than 1 billion have hypertension, and more than 500 million have either diabetes or the prediabetes category, impaired glucose tolerance (IGT) [Hossain et al. 2007]. As a consequence of these alarming figures, the prevalence of the metabolic syndrome is also (not surprisingly) very common, with almost 50 million individuals affected in the USA alone [Ford, 2005]. In view of the incredible numbers of people affected by these chronic risk states and associated complications, pharmaceutical companies are exploring the role of existing therapies and are developing many new drugs targeting the metabolic syndrome. Indeed, one review on new therapies for the metabolic syndrome listed the number of potential ‘drug targets’ at nearly 10,000 (i.e. targets in the genome, proteome, transcriptome, etc.) [Flordellis et al. 2005]. However, no drugs are currently approved for the indication of metabolic syndrome [Food and Drug Administration, 2007; Heal et al. 2009].

Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)

Subjects with type 1 diabetes mellitus (T1DM) eventually develop insulin resistance and other features of T2DM such as cardiovascular disorders. The exact mechanism has been not been completely understood. In this study, we tested the hypothesis that excessive or inappropriate exposure to insulin is a primary mediator of insulin resistance in T1DM. We found that continuous exposure of mice with non-obese diabetes to insulin detemir, which is similar to some current conventional treatment of human T1DM, induced severe insulin resistance, whereas untreated hyperglycemia for the same amount of time (2 weeks) did not cause obvious insulin resistance. Insulin resistance was accompanied by decreased mitochondrial production as evaluated by mitochondrial DNA and levels of transcripts and proteins of mitochondrion-associated genes, increased ectopic fat accumulation in liver and skeletal muscle (gastrocnemius) evaluated by measurements of triglyceride content, and elevated oxidative stress detected by the GSH/GSSG ratio. Prolonged exposure of cultured hepatocytes to insulin induced significant insulin resistance, whereas the same length of exposure to a high level of glucose (33 mm) did not cause obvious insulin resistance. Furthermore, our results showed that prolonged exposure to insulin caused oxidative stress, and blockade of mitochondrion-derived oxidative stress by overexpression of manganese-superoxide dismutase prevented insulin resistance induced by the prolonged exposure to insulin. Together, our results show that excessive exposure to insulin is a primary inducer of insulin resistance in T1DM in mice.