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Insulin resistance and obesity,vegetarian diet before and after workout,crohn's liquid diet recipes,most effective diet plan 2015 - Plans Download

CMR Short Reviews The Concept of CMR Historical background on global cardiometabolic risk, epidemiological aspects of obesity and type 2 diabetes, ABCs of cardiovascular disease risk factors, intra-abdominal adiposity, metabolic syndrome and contribution to cardiometabolic risk. One of the most common metabolic complications of intra-abdominal (visceral) obesity is insulin resistance, a condition in which insulin no longer functions effectively.
This section explains the link between intra-abdominal obesity and insulin resistance in adipose and other insulin-responsive tissues, namely skeletal muscle and the liver, and how insulin resistance affects type 2 diabetes and cardiovascular disease (CVD) risk.
Between meals, and especially at night, there is no incoming glucose from external sources, and the body must maintain blood glucose from endogenous sources.
Glucose is carried freely in the blood and readily crosses endothelial cells that line blood capillaries to reach parenchymal cells. Insulin, a hormone secreted by the beta cells of the pancreatic islets of Langerhans, plays a number of crucial roles in glucose homeostasis.
Insulin is secreted by pancreatic beta cells into the portal circulation (draining into the liver) at a low rate in the fasted state.
The postprandial rise in insulin alters three major metabolic pathways related to glucose homeostasis: 1) insulin increases glucose uptake by insulin-sensitive tissues, mainly skeletal muscle, 2) insulin inhibits fatty acid release from adipose tissue, allowing glucose to become a major energy fuel, and 3) insulin decreases hepatic production of glucose, a sensible move given the arrival of dietary glucose. In the fasted state, adipose tissue hydrolyzes some of its triglycerides into glycerol (a precursor of liver gluconeogenesis) and fatty acids (an important source of fuel for ATP production in various tissues). One of the major conditions caused by excess intra-abdominal adipose tissue is insulin resistance, defined as the inability of insulin to perform many of its major metabolic functions.
Key studies conducted in the early 1990s clearly established that it is the intra-abdominal component of excess fat, and not total fat, that is strongly associated with impaired insulin action (8, 9).
Under conditions that favour obesity, fat cells accumulate lipids to store excess energy and expand in size, a process known as hypertrophy.
Macrophage infiltration correlates with adipocyte size (17), and, as noted above, the events that trigger attraction of immune cells in the vicinity of expanding adipose cells appear to be relatively specific to intra-abdominal fat (18). Because lipolysis and inflammation are particularly severe in expanding intra-abdominal adipose depots and because these depots are partly drained by the portal vein, it is not surprising that the liver is a prime target for the problems caused by a dysfunctional intra-abdominal adipose tissue. Excess fatty acids and proinflammatory cytokines from adipose tissue reach skeletal muscle through the systemic circulation, where they trigger insulin resistance. Normally, fatty acids taken up by skeletal muscle and the liver are either used as energy substrates to produce ATP through beta-oxidation or safely stored in the form of inert triglycerides. Together with fatty acid metabolites, proinflammatory adipokines that are overproduced by expanding intra-abdominal fat and other possible sources (see above) also play a role in the development of insulin resistance. In individuals with robust pancreatic beta cells, insulin resistance may become more severe, with the pancreas remaining able to produce and secrete ever-more insulin to compensate for its deteriorating peripheral action. The mildest form of glucose dysregulation caused by insulin resistance is impaired glucose tolerance (IGT). In some individuals, whole-body insulin resistance and beta cell damage become so severe that the residual insulin that may still be produced has little or no effect on glucose handling. Despite the fact that insulin resistance is a risk factor for type 2 diabetes, most insulin-resistant individuals will never develop type 2 diabetes. Hyperglycermia (be it postprandial in IGT or daylong in IFG and type 2 diabetes) has several harmful effects in and of itself.
The chronic hyperinsulinemia needed to compensate for insulin resistance also has harmful health consequences.
Beyond blood levels of glucose and insulin, it is insulin resistance that appears to bear most of the blame for the heightened type 2 diabetes and CVD risk that comes with intra-abdominal obesity. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial.
The content of this website is provided for educational and informational purposes only and is not to be used for medical advice, diagnosis or treatment. In the fasted state, the liver provides the bulk of glucose to the bloodstream through glycogenolysis and gluconeogenesis. It is generally accepted that insulin resistance is a major cause of many components of the metabolic syndrome, including dysregulation of glucose homeostasis, which can lead to type 2 diabetes. A brief overview of how insulin regulates blood glucose is provided in order to place intra-abdominal obesity-related insulin resistance in proper context. Virtually all body tissues use a mixture of glucose and fatty acids as substrates for ATP production, with some (brain, red blood cells) using glucose almost exclusively. Although the glucose molecule is quite simple, it cannot cross the cell plasma membrane on its own and must be helped by membrane proteins called glucose transporters (GLUT).
Not only does it act directly on glucose uptake by insulin-sensitive tissues and on hepatic glucose production, it also acts indirectly by modulating adipose and liver lipid metabolism.
The arrival of nutrients absorbed from the gut into the blood triggers a sharp rise in insulin output from the pancreas.
Following are the major mechanisms by which these important insulin-mediated metabolic changes take place. The postprandial rise in insulin acts on adipose tissue to inhibit lipolysis, which reduces the release of glycerol and fatty acids and encourages tissues such as skeletal muscle to use glucose as a fuel source. Most evidence points to a cause-and-effect relationship between excess intra-abdominal fat and insulin resistance, as well as between insulin resistance and the health complications associated with intra-abdominal obesity.
The glucose and insulin response to a glucose load was measured in men with identical amounts of total body fat and who were grouped according to whether they had low or high amounts of intra-abdominal fat (determined by computed tomography).
The outcome of this process is adipose tissue inflammation, which is maintained by feed-forward cross-talk between the infiltrated immune cells and the adipocytes (19, 20) (Figure 4).


Hepatic lipid accumulation (steatosis) often accompanies and parallels weight gain and visceral obesity. Although fatty acids released by intra-abdominal fat likely contribute to steatosis and insulin resistance in the liver, their contribution to systemic fatty acid levels and the amount of lipids that reach skeletal muscle is less clear. When fatty acids are in excess (a condition called ectopic fat accumulation), however, cells overproduce fatty acid metabolites such as fatty-acyl CoA, diacylglycerol, and ceramides. The mechanisms that link proinflammatory cytokines and insulin signalling are complex and not fully understood.
In insulin-resistant subjects, glucose uptake by skeletal muscle, a major site of its clearance, does not increase after a meal, which leaves more glucose in the bloodstream. As with fatty acids, excess glucose contributes to insulin resistance and is toxic to beta cells (glucotoxicity) (27, 28). Insulin resistance is at the very core of many components of the metabolic syndrome, including major CVD risk factors such as dyslipidemia, hypertension, and type 2 diabetes.
However, targeting the fundamental cause of obesity-related insulin resistance by reducing intra-abdominal fat undoubtedly remains a key therapeutic objective.
The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.
MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity.
Mesenteric adipose tissue-derived monocyte chemoattractant protein-1 plays a crucial role in adipose tissue macrophage migration and activation in obese mice.
Receptor for advanced glycation end products and the cardiovascular complications of diabetes and beyond: lessons from AGEing. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. This is not surprising given that insulin is a hormone that plays a critical role in controlling carbohydrate, lipid, and protein metabolism and influences a host of other cellular functions in many organs. A primary source of hepatic glucose is glycogen, a glucose polymer that is synthesized when plenty of glucose is available and provides a ready source of energy when necessary. Normally, insulin strongly inhibits lipolysis by interfering with the action of hormone-sensitive lipase, a major lipolytic enzyme (6). It is therefore important to understand how intra-abdominal obesity leads to insulin resistance. Men with low intra-abdominal fat had a glucose and insulin response to the oral glucose challenge that was similar to that of a lean, control group of men. The adipocyte stress signal (MCP-1) and its monocyte receptor interact to trigger a complex set of events that brings monocytes close to the adipocytes that initiated the signal, where they evolve into macrophages. The inflammation associated with intra-abdominal obesity is discussed in more detail in another section. Some or all of these metabolites (depending on the tissue) trigger the activation of protein kinases that phosphorylate proteins involved in insulin signalling on their serine or threonine residues, rather than on tyrosine residues as normally occurs.
In the insulin-resistant liver, insulin is unable to reduce de novo glucose production (gluconeogenesis) and glucose export to the circulation, which hinders the postprandial reduction in hepatic glucose output and further increases circulating glucose.
In other individuals, however, pancreatic beta cells do not continue compensating with extra insulin over time.
However, epidemiological data shows that, even if blood sugar levels are normal, the CVD risk resulting from the metabolic abnormalities associated with the metabolic syndrome (of which insulin resistance is a central component) increases significantly. High insulin has also been shown to have a direct, negative impact on endothelial function and vascular biology, which raises overall cardiovascular health risk (34).
If the -cells are normal, their function and mass increase in response to this increased secretory demand, leading to compensatory hyperinsulinaemia and the maintenance of normal glucose tolerance. Insulin also reduces liver glucose production after a meal and reduces fatty acid release by adipose tissue. Most transporters function on their own, but GLUT4, the major isoform expressed in adipose tissue and skeletal muscle, requires insulin to function properly. Insulin also inhibits adipose tissue lipolysis, which reduces fatty acid delivery from intra-abdominal adipose tissue to the liver, lowers hepatic fatty acid oxidation rates, and thereby inhibits gluconeogenesis. Men with high intra-abdominal fat had statistically greater glucose and insulin responses than men in the other two groups. TNF-α interferes with insulin signalling, decreasing glucose uptake, reducing insulin-mediated inhibition of lipolysis and fatty acid release into the circulation, and lowering the production of enzymes involved in lipid uptake and storage, which reduces the ability of adipocytes to clear lipids from the circulation. Intra-abdominal obesity is also characterized by hypertriglyceridemia, which may increase fatty acid delivery to muscle through local action of the lipoprotein lipase. The final outcome is that the body is less able to tailor glucose production and clearance to the prevailing metabolic conditions. A detailed review of the causes and mechanisms of beta cell deterioration is beyond the scope of this section. The increased glucose indicates that the pancreas is unable to produce enough insulin to fully handle the glucose load within a normal timeframe.
By contrast, susceptible -cells have a genetically determined risk, and the combination of increased secretory demand and detrimental environment result in -cell dysfunction and decreased -cell mass, resulting in progression to impaired glucose tolerance, followed, ultimately, by the development of type 2 diabetes. A second important source of glucose comes from the synthesis of new glucose molecules from precursors such as glycerol (from hydrolysis of triglycerides in adipose tissue), lactate (from muscle anaerobic glycolysis), and some amino acids (from the breakdown of muscle proteins) through a process called gluconeogenesis. In rodent models, invalidation of the MCP-1 gene or that of its receptor CCR-2 partially protects against diet-induced insulin resistance (15, 16). A number of factors appear to cause the changes in adipokine production, including TNF-α, MCP-1, and other cytokines derived from local macrophages.


With regard to proinflammatory cytokines, they may come from intra-abdominal fat depots and the liver (20) as well as from adipocytes found in the vicinity of skeletal muscle fibres.
Obesity is frequently associated with IGT, and studies have clearly established that it is excess intra-abdominal fat rather than excess overall fat that is associated with the condition (8-11). In addition, prolonged, high levels of glucose can cause retinopathy, neuropathy, nephropathy, and CVD to a lesser extent (31-33). Instead, it is insulin resistance that must be the priority target when treating insulin homeostasis problems. Insulin-independent GLUT1 is also expressed in adipose tissue and muscle and mediates basal glucose uptake. Other nutrients, including some fatty acids and amino acids, are also insulin secretagogues.
The postprandial rise in insulin therefore favours the uptake of blood glucose by skeletal muscle (and to a lesser extent by adipose tissue) and gradually returns blood glucose to fasting levels. The stress response includes the following: 1) activation of pathways (c-Jun NH2-terminal kinase (JNK) and NFkB, two master regulators of inflammation) that encourage the production of proinflammatory cytokines, 2) overproduction of reactive oxygen species (oxidative stress), and 3) production of signals for programmed cell death (apoptosis). Lipid accumulation in the liver is not a benign condition and it can evolve into steatohepatitis or even cirrhosis in susceptible individuals.
However, defects in local mitochondrial function that impair fatty acid oxidation have also been held out as causes of intracellular accumulation of insulin resistance-promoting fatty acid derivatives (23). Though not fully understood, genetic predisposition and environmental factors determine beta cell fragility upon exposure to stress. This process triggers macrophages that, together with the enlarged adipocytes, locally secrete insulin-resistance-promoting molecules. The rate of gluconeogenesis is driven mainly by the availability of precursors (which increase in the fasted state) and by the rate of fatty acid oxidation in the liver (also increased in the fasted state).
Insulin secretion is further enhanced postprandially by the increase in gut hormones called incretins. The stress response has two major outcomes: 1) insulin resistance first develops in the adipocyte, which reduces glucose uptake and lessens inhibition of lipolysis and 2) the stressed adipocyte secretes molecules that chemically attract cells of the immune system, mainly monocytes (a type of white blood cell), that can become macrophages once within a tissue.
In addition, the inflamed liver secretes proinflammatory cytokines (TNF-α, IL-6, C-reactive protein) that are thought to help maintain the proinflammatory environment associated with intra-abdominal obesity (20).
If insulin becomes less efficient at handling glucose, pancreatic beta cells become more active and secrete more insulin to compensate for insulin resistance.
Hypertrophied insulin-resistant intra-abdominal adipocytes release more fatty acids and proinflammatory adipokines into the bloodstream. Proper glucose disposal is needed to maintain stable glycemia, and this requires efficient insulin action on GLUT4 function, mainly in skeletal muscle (2, 3).
Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the most important, and their secretion is triggered by food ingestion. Normally, resident macrophages protect tissues by taking up and eliminating potentially harmful cell debris and toxins. Several factors contribute to islet compensation, including increased glucose oxidation within the beta cell, increased fatty acid signalling (because of enhanced release by intra-abdominal adipose tissue), sensitivity to intestinal incretins, and increased parasympathetic nervous system activity in islets (24). The portal circulation carries these to the liver where they promote steatosis, insulin resistance, and local inflammation.
The brain also senses changes in blood glucose and modulates insulin secretion via parasympathetic and sympathetic nerve fibres to the pancreas (4).
Although insulin resistance affects many metabolic pathways, the discussion that follows is limited to glucose metabolism. Compensatory hyperinsulinemia is able, at least for a while, to keep blood glucose levels within the normal range in the fasted and postprandial states.
Each 1% decrease in blood HbA1C reduces the risk of diabetes-related complications by about 21%, diabetes-related mortality by 21%, myocardial infarction by 14%, and microvascular complications by 37% (31). The systemic circulation carries fatty acids and proinflammatory molecules to skeletal muscle where they promote lipid accumulation, insulin resistance, and local inflammation. This is because the extra insulin compensates for its reduced ability to stimulate muscle (and adipose tissue) glucose uptake and reduce hepatic glucose production. Insulin resistance also affects the function of other systems and organs, including endothelial cells and cells of the vascular wall.
This encourages rather than inhibits inflammation and harms rather than protects the adipocyte, as discussed below (14).
Only assessing insulin levels in the fasted state and in response to glucose or mixed-food intake can indicate the existence of insulin resistance, which will appear as hyperinsulinemia in the postprandial state or in both fasting and postprandial states, depending on the severity of insulin resistance. Insulin resistance is believed to play a role in the development of many metabolic abnormalities that define the metabolic syndrome.
It is also believed to be a strong link between intra-abdominal obesity and increased risk of type 2 diabetes and CVD. Targeting the fundamental cause of obesity-related insulin resistance by reducing intra-abdominal fat mass remains an important therapeutic objective.



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