Lipotoxicity treatment,

Metformin in Nonalcoholic Steatohepatitis: A Randomized Controlled Trial

Introduction Type 2 diabetes mellitus T2DM results from a combination of genetic and environmental factors that induces tissue insulin resistance and beta-cell failure.

Open in a separate window Of study subjects, 13 in the metformin and 13 in the placebo group lipotoxicity treatment overweight and received weight loss instructions. The decrease in BMI was not significantly different between overweight subjects who received weight loss instructions and normal weight subjects who received no instructions. However, there was no significant difference in the magnitude of decrease in liver enzymes between the two treatment groups. Changes in other parameters were not significant; neither within each of the treatment groups nor between them, and neither within the entire group of subjects. Biopsy was conducted on all 33 subjects before treatment and 8 subjects after treatment completion 6 subjects in the metformin and 2 in the placebo groups.

The purpose of the present chapter is to focus on beta-cell function under physiological conditions and to review lipotoxicity treatment potential beta-cell failure mechanisms, the place in natural history of T2DM and implication for treatment of beta-cell dysfunction. Advertisement 2. Normal beta-cell function The main role of beta-cell is to synthesize and secrete insulin in order to maintain circulating glucose levels within physiological range.

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Although there exist several triggers of insulin secretion like nutrients amino acids such as leucine, glutamine in combination with leucine, nonesterified fatty acidhormones, neurotransmitters and drugs sulfonylurea, glinidesglucose lipotoxicity treatment the main physiological insulin secretagogue [ 1 ].

According to the most widely accepted hypothesis, insulin secretion is a multistep process initiated with glucose transport into beta-cell through specific transporters GLUT1 and GLUT2 in particular and phosphorylation by glucokinase, which directs metabolic flux through glycolysis, producing pyruvate as the terminal product of the pathway [ 2 ].

Pyruvate then enters the mitochondria and is decarboxylated to acetyl-CoA, which enters the tricarboxylic acid cycle. The tricarboxylic acid cycle proper begins with a condensation of acetyl-CoA and oxaloacetate, to form citrate, a reaction catalysed by citrate synthase.

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Aconitase catalyses the convertion of citrate to isocitrate. NAD-linked isocitrate dehydrogenase then oxidatively decarboxylates isocitrate to form α-ketoglutarate. The α-ketoglutarate is oxidised to succinyl-CoA in a reaction catalysed by α-ketoglutarate dehydrogenase.

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Succinate dehydrogenase catalyses the oxidation of succinate to fumarate. Lipotoxicity treatment pathways enable the recycling of the tricarboxylic acid cycle intermediates into and out of mitochondrion, allowing a continuous production of intracellular messengers [ 3 - 5 ]. These three cycles share, as a common terminal step, the conversion of malate to pyruvate concomitant with the production of cytosolic NADPH.

Malate exits the mitochondria to the cytoplasm where it is subsequently oxidised to pyruvate concomitant with the production of NADPH by cytosolic malic enzyme. Pyruvate then re-enters mitochondria for the next round of carboxylation by pyruvate carboxylase [ 3 - 5 ].

Most of lipotoxicity treatment weight gain happens during chemotherapy, 2 main mechanisms being behind this process: decreased metabolism and decreased ability to perceive satiety. The decrease in metabolic rate happens because - besides the increased muscular catabolism generated by the decreased estrogen - the muscle mass is gradually lost through the sedentariness and inadequate intake of protein to sustain muscle mass. And also, many breast cancer patients either develop dyslipidemia during chemotherapy, either develop insulin resistance - both causing leptin resistance: expressed as decreased ability to perceive satiety and paradoxal hunger dissociated of the blood sugar level, sometimes even shortly after eating a full meal.

Citrate then exits the mitochondrion to the cytoplasm where it is converted back to oxaloacetate and acetyl-CoA by ATP-citrate lyase. Oxaloacetate is converted by cytosolic malate dehydrogenase lipotoxicity treatment malate before being converted to pyruvate by malic enzyme. Malonyl-CoA inhibits carnitine palmitoyl transferase-1, which transports fatty acyl-CoA into mitochondria where it is oxidised, leading parazitoza copii increase in long-chain acyl-CoAs in the cytosol [ 3 - 5 ].

The NADPH oxidase complex in the plasma membrane is also activated through protein kinase C, which is activated by fatty acid derived signalling molecules.

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Under physiological conditions, there is a hyperbolic relation between insulin secretion and insulin sensitivity. Classically, glucose-stimulated insulin secretion is characterized by a first phase, which ends within a few minutes, and prevents or decreases glucose concentration and a more prolonged second phase in which insulin is released proportionally to the plasma glucose [ 9 ].

In addition, it has been demonstrated that the release of insulin is oscillatory, with relatively stable rapid pulses occurring at every minutes which are superimposed lipotoxicity treatment low-frequency oscillations [ 10 ].

In humans the amplitude of insulin oscillations is fold higher in the portal vein than in the systemic circulation implying preferential hepatic extraction of insulin pulses.

1. Introduction

Research to further understand the roles of these pathways may provide strategies for future therapies of T2DM. Place of beta-cell dysfunction in natural history of type 2 diabetes T2DM is a progressive condition caused by genetic and environmental factors that induce tissue insulin resistance and beta-cell dysfunction.

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Several lines of evidence indicated that there is no hyperglycemia without beta-cell dysfunction [ 1314 ]. In most subjects with obesity-induced insulin resistance developing increased insulin secretion, insulin gene expression and beta-cell mass, these compensatory mechanisms can succeed to maintain glucose homeostasis and avoidance of diabetes mellitus [ 13 - 15 ].

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Progression from beta-cell compensation to failure in the face of lipotoxicity treatment insulin resistance occurs in a subset of genetically predisposed individuals who fail to adequately compensate for the increased insulin demand, leading to glucolipotoxicity. In this phase insulin secretion in relation to the degree lipotoxicity treatment insulin resistanceinsulin gene expression and beta-cell mass are reduced, causing increased levels of glucose and free fatty acids [ 1314 ].

In most cases, almost half of the women with Lipotoxicity treatment have IR which is triggered by inflammation, glucotoxicity and lipotoxicity. In this work was conducted a systematic review of all the papers that used metabolomics for detecting IR biomarkers in PCOS women. The exclusion criteria were: reviews, study population with women bellow 18 years of age, studies including animals and articles not in English, remaining 4 records. The results from the literature shown that phosphatidylcholines were decreased in IR PCOS women when compared to controls. Nonetheless, transhexenoylcoa, linoleic acid, leucine, myristic acid and palmitic acid regarding lipid metabolism and tyrosine, lysine, phenylalanine a-aminoadipic acid regarding amino acid metabolism were also corelated to IR in PCOS women when compared with healthy or IR controls.

In T2DM, the typical beta-cell functional alterations are represented by: change of threshold for insulin secretion triggering lipotoxicity treatment relatively selective loss of responsivity to glucose compared to other insulin secretagogues like arginin or glibenclamide alteration of insulin secretion oscillatory patterns with impairment of both high frequency and ultradian oscillations reduced or absent first phase insulin secretion initially to intravenous glucose and then to mixed meal ingestion prolongation of second phase of insulin secretion gradual, time-dependent irreversible damage to cellular components of insulin production [ 913 - 18 ].

Longitudinal studies in humans have clearly demonstrated that beta-cell function deteriorates during the years.

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The accelerated beta-cell dysfunction is the consequence of glucolipotoxicity. Consequent deterioration in metabolic equilibrium with increasing levels of glucose and free fatty acids, enhance and accelerate beta-cell dysfunction, lead to beta-cell apoptosis that does not seems to be adequately compensated by regenerative process and subsequent decrease of beta-cell mass.

INTRODUCTION

Potential mechanism and modulators of beta-cell failure The main focus of the present chapter is on potential beta-cell failure mechanisms in T2DM. The initial alterations in beta-cell function are likely to reflect intrinsic defects, whereas the accelerated beta-cell dysfunction which mainly occurs after the development of overt hyperglycemia is the consequence of glucolipotoxicity [ 21 ].

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This reflects a genetic predisposition for beta-cell defect, whereas the subsequent beta-cell failure may be a consequence of concomitant environmental conditions. Schematic representation of the role of cellular dysfunction in the natural history of T2DM is included in Figure 1.

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Figure 1. Place of beta-cell dysfunction in natural history of type 2 diabetes 5. Genetic factors Several genes associated with increased risk of developing T2DM have been identified in genome-wide association studies [ 22 ].

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There were detected several genetic variants lipotoxicity treatment genes that confer risk of diabetes by interfering with next three mechanisms: reduction of insulin secretion.

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