Liver fat in the metabolic syndrome and type 2 diabetes

Introduction: The epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). However, not all obese subjects develop these metabolic abnormalities. Hepatic fat accumulation is related to hepatic insulin resistance, which in turn leads to hyperglycemia, hypertriglyceridemia, and a low HDL cholesterol con-centration. The present studies aimed to investigate 1) how intrahepatic as compared to intramyocellular fat is related to insulin resistance in these tissues and to the metabolic syndrome (Study I); 2) the amount of liver fat in subjects with and without the metabolic syndrome, and which clinically available markers best reflect liver fat content (Study II); 3) the effect of liver fat on insulin clearance (Study III); 4) whether type 2 diabetic patients have more liver fat than age-, gender-, and BMI-matched non-diabetic subjects (Study IV); 5) how type 2 diabetic patients using exceptionally high doses of insulin respond to addition of a PPARγ agonist (Study V). Subjects and methods: The study groups consisted of 45 (Study I), 271 (Study II), and 80 (Study III) non-diabetic subjects, and of 70 type 2 diabetic patients and 70 matched control subjects (Study IV). In Study V, a total of 14 poorly controlled type 2 diabetic patients treated with high doses of insulin were studied before and after rosiglitazone treatment (8 mg/day) for 8 months. In all studies, liver fat content was measured by proton magnetic resonance spectroscopy, and sub-cutaneous and intra-abdominal fat content by MRI. In addition, circulating markers of insulin resistance and serum liver enzyme concentrations were determined. Hepatic (i.v. insulin infusion rate 0.3 mU/kg∙min combined with [3-3H]glucose, Studies I, III, and V) and muscle (1.0 mU/kg min, Study I) insulin sensitivities were measured by the euglycemic hyperinsulinemic clamp technique. Results: Fat accumulation in the liver rather than in skeletal muscle was associated with features of insulin resistance, i.e. increased fasting serum (fS) triglycerides and decreased fS-HDL cholesterol, and with hyperinsulinemia and low adiponectin concentrations (Study I). Liver fat content was 4-fold higher in subjects with as compared to those without the metabolic syndrome, independent of age, gender, and BMI. FS-C-peptide was the best correlate of liver fat (Study II). Increased liver fat was associated with both impaired insulin clearance and hepatic insulin resistance independent of age, gender, and BMI (Study III). Type 2 diabetic patients had 80% more liver fat than age-, weight-, and gender-matched non-diabetic subjects. At any given liver fat content, S-ALT underestimated liver fat in the type 2 diabetic patients as compared to the non-diabetic subjects (Study IV). In Study V, hepatic insulin sensitivity increased and glycemic control improved significantly during rosiglitazone treatment. This was associated with lowering of liver fat (on the average by 46%) and insulin requirements (40%). Conclusions: Liver fat is increased both in the metabolic syndrome and type 2 diabetes independent of age, gender, and BMI. A fatty liver is associated with both hepatic insulin resistance and impaired insulin clearance. Rosi-glitazone may be particularly effective in type 2 diabetic patients who are poorly controlled despite using high insulin doses.Metabolisella oireyhtymällä tarkoitetaan sydän- ja verisuonisairauksien vaaratekijöiden kasaumaa, johon kuuluu keskivartalolihavuuden lisäksi kohonnut verenpaine, paastosokeri ja poikkeavat rasva-arvot (kohonneet triglyseridit ja matala hyvä (HDL)-kolesteroli). Vaikka metabolinen oireyhtymä ja tyypin 2 diabetes ovat yleisempiä lihavilla kuin normaalipainoisilla, on epäselvää, miksi joillekin lihaville näitä häiriöitä ei kehity. Insuliini estää normaalisti maksan sokerin ja rasvojen tuotantoa, mutta rasvaisessa maksassa nämä vaikutukset ovat heikentyneet. Tässä väitöskirjassa selvitettiin, kuinka rasvainen maksa on henkilöillä, joilla on metabolinen oireyhtymä tai tyypin 2 diabetes, ja mikä veren merkkiaine tai kehon koostumuksen poikkeavuus parhaiten heijastaa maksan rasvapitoisuutta. Lisäksi tutkittiin, miten hoito insuliiniherkiste-lääkeaineella (glitatsonilla) vaikuttaa poikkeuksellisen paljon insuliinia (keskimäärin yli 200 yks/vrk) vaativien tyypin 2 diabeetikoiden maksan rasvapitoisuuteen, insuliinitarpeeseen ja hoitotasapainoon. Kaikissa osatöissä maksan rasvapitoisuus mitattiin magneettitutkimuksella. Insuliinin vaikutusta maksassa ja lihaksissa mitattiin suorilla menetelmillä. Tämän lisäksi mitattiin seerumin rasva-arvoja ja paastoinsuliini- ja maksaentsyymipitoisuuksia. Metabolinen oireyhtymä liittyi maksan- muttei lihaksensisäisen rasvan kertymiseen. Maksan rasvaprosentti oli neljä kertaa suurempi henkilöillä, joilla oli metabolinen oireyhtymä kuin henkilöillä, joilla oireyhtymää ei ollut. Seerumin paastoinsuliinin ja C-peptidin pitoisuudet heijastivat parhaiten maksan rasvapitoisuutta. Insuliinin vaikutus oli alentunut henkilöillä, joilla maksan rasvapitoisuus oli koholla. Tyypin 2 diabeetikoilla todettiin olevan merkittävästi enemmän rasvaa maksassa kuin yhtä lihavilla henkilöillä, joilla ei ollut diabetesta. Seerumin maksa-arvot aliarvioivat maksan rasvan määrää tyypin 2 diabeetikoilla. Insuliiniherkiste vähensi maksan rasvapitoisuuden ja insuliinitarpeen puoleen verrattuna tilanteeseen ennen hoitoa. Insuliiniherkistehoidon aikana sokeritasapaino ja maksan insuliiniherkkyys paranivat. Maksa on rasvoittunut henkilöillä, joilla on metabolinen oireyhtymä, ja etenkin potilailla, joilla on tyypin 2 diabetes. Insuliiniherkistehoito vaikuttaa tehokkaalta sellaisilla tyypin 2 diabeetikoille, joilla on korkea insuliinitarve rasvamaksasta johtuen

Multivariate multi-way analysis of multi-source data

Motivation: Analysis of variance (ANOVA)-type methods are the default tool for the analysis of data with multiple covariates. These tools have been generalized to the multivariate analysis of high-throughput biological datasets, where the main challenge is the problem of small sample size and high dimensionality. However, the existing multi-way analysis methods are not designed for the currently increasingly important experiments where data is obtained from multiple sources. Common examples of such settings include integrated analysis of metabolic and gene expression profiles, or metabolic profiles from several tissues in our case, in a controlled multi-way experimental setup where disease status, medical treatment, gender and time-series are usual covariates

Nine-year incident diabetes is predicted by fatty liver indices: the French D.E.S.I.R. study

<p>Abstract</p> <p>Background</p> <p>Fatty liver is known to be linked with insulin resistance, alcohol intake, diabetes and obesity. Biopsy and even scan-assessed fatty liver are not always feasible in clinical practice. This report evaluates the predictive ability of two recently published markers of fatty liver: the Fatty Liver Index (FLI) and the NAFLD fatty liver score (NAFLD-FLS), for 9-year incident diabetes, in the French general-population cohort: Data from an Epidemiological Study on the Insulin Resistance syndrome (D.E.S.I.R).</p> <p>Methods</p> <p>At baseline, there were 1861 men and 1950 women, non-diabetic, aged 30 to 65 years. Over the follow-up, 203 incident diabetes cases (140 men, 63 women) were identified by diabetes-treatment or fasting plasma glucose ≥ 7.0 mmol/l. The FLI includes: BMI, waist circumference, triglycerides and gamma glutamyl transferase, and the NAFLD-FLS: the metabolic syndrome, diabetes, insulin, alanine aminotransferase, and asparate aminotransferase. Logistic regression was used to determine the odds ratios for incident diabetes associated with categories of the fatty liver indices.</p> <p>Results</p> <p>In comparison to those with a FLI < 20, the age-adjusted odds ratio (95% confidence interval) for diabetes for a FLI ≥ 70 was 9.33 (5.05-17.25) for men and 36.72 (17.12-78.76) for women; these were attenuated to 3.43 (1.61-7.28) and 11.05 (4.09 29.81), after adjusting on baseline glucose, insulin, hypertension, alcohol intake, physical activity, smoking and family antecedents of diabetes; odds ratios increased to 4.71 (1.68-13.16) and 22.77 (6.78-76.44) in those without an excessive alcohol intake. The NAFLD-FLS also predicted incident diabetes, but with odds ratios much lower in women, similar in men.</p> <p>Conclusions</p> <p>These fatty liver indexes are simple clinical tools for evaluating the extent of liver fat and they are predictive of incident diabetes. Physicians should screen for diabetes in patients with fatty liver.</p

Serum lipids and their associations with viral levels and liver disease severity in a treatment‐naïve chronic hepatitis C type 1‐infected cohort

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94280/1/j.1365-2893.2010.01394.x.pd

Phosphodiesterase 3B Is Localized in Caveolae and Smooth ER in Mouse Hepatocytes and Is Important in the Regulation of Glucose and Lipid Metabolism

Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein 1c and hydroxyl-3-methylglutaryl coenzyme A reductase. In conclusion, hepatocyte PDE3B is localized in caveolae and smooth endoplasmic reticulum and plays important roles in the regulation of glucose, triglyceride and cholesterol metabolism. Dysregulation of PDE3B could have a role in the development of fatty liver, a condition highly relevant in the context of type 2 diabetes

Iron and steatohepatitis.

As the main iron storage site in the body and the main source of the iron-regulatory hormone, hepcidin, the liver plays a pivotal role in iron homeostasis. A variable degree of hepatic iron accumulation has long been recognized in a number of chronic liver diseases. Both alcoholic and non-alcoholic steatohepatitis display increased iron deposits in the liver, with an hepatocellular, mesenchymal, or mixed pattern, and recent reports have documented a concomitant aberrant hepcidin expression that could be linked to different coincidental pathogenic events (e.g. the etiological agent itself, necroinflammation, metabolic derangements, genetic predisposition). The present study reviews the pathogenic mechanisms of iron accumulation in steatohepatitis during alcoholic and non-alcoholic liver disease and the role of excess iron in chronic disease progression

The effects of insulin resistance on individual tissues: an application of a mathematical model of metabolism in humans

Whilst the human body expends energy constantly, the human diet consists of a mix of carbohydrates and fats delivered in a discontinuous manner. To deal with this sporadic supply of energy, there are transport, storage and utilisation mechanisms, for both carbohydrates and fats, around all tissues of the body. Insulin-resistant states such as type 2 diabetes and obesity are characterised by reduced efficiency of these mechanisms. Exactly how these insulin-resistant states develop, for example whether there is an order in which tissues become insulin resistant, is an active area of research with the hope of gaining a better overall understanding of insulin resistance. In this paper we use a previously derived system of 12 first-or der coupled differential equations that describe the transport between, and storage in, different tissues of the human body. We briefly revisit the derivation of the model before parametrising the model to account for insulin resistance. We then solve the model numerically, separately simulating each individual tissue as insulin resistant, and discuss and compare these results, drawing three main conclusions. The implications of these results are in accordance with biological intuition. First, insulin resistance in a tissue creates a knock-on effect on the other tissues in the body, whereby they attempt to compensate for the reduced efficiency of the insulin resistant tissue. Secondly, insulin resistance causes a fatty liver; and the insulin resistance of tissues other than the liver can cause fat to accumulate in the liver. Finally, although insulin resistance in individual tissues can cause slightly reduced skeletal-muscle metabolic flexibility, it is when the whole body is insulin resistant that the biggest effect on skeletal muscle flexibility is see