Insulin Resistance and Obesity - Παχυσαρκία και αντίσταση στη δράση της ινσουλίνης

Η παχυσαρκία αποτελεί σήμερα τη συχνότερη αιτία αντίστασης στη δράση της ινσουλίνης, η οποία, εκτός από το ότι προδιαθέτει στην εμφάνιση διαβήτη 2, αποτελεί και το κλειδί για το σύνολο πρακτικά των καρδιο-αγγειακών νόσων.
Πιο αναλυτικά στοιχεία σε μορφή .pdf μπορείτε να έχετε στο έγγραφο-παρουσίαση που σας παραθέτουμε.
Αναλυτικό Άρθρο (pdf)

Το άρθρο στα Αγγλικά
Obesity and especially increased accumulation of visceral adipose tissue is associated with increased risk for type 2 diabetes and CVD. The main causative factor for morbidity and mortality in those subjects is metabolic syndrome with central component Insulin resistance.
Obesity is the most common cause of metabolic syndrome and weight loss offers the only holistic management of the syndrome.
There are many insulin resistance definitions. I prefer this one that is proposed by E.A. Ferranini
“Reduced sensitivity of glucose uptake to insulin stimulation, sensed by the beta-cell through elevated plasma glucose levels”
There are many differences between the usual hormone system and the insulin action system.
The first difference is that there are normal conditions characterised from insulin resistance: Puberty and pregnancy. In puberty, the compensatory hyperinsulinaemia is conductive to protein anabolism. In pregnancy, there is a glucose saving in order to be channelled to the foetus.
The second main difference is that in all the other hormonal systems the biological actions are characterised by generalised failure. In Insulin resistance states there is a defect on glucose disposal, but the action of insulin on sympathetic nervous system is increased, as well as sodium re-absorption and cellular potassium uptake.
An other difference is that in insulin resistance states the defect is usually at the post-receptor levels. This means that the defect is a malfunction of the signal transduction machinery. Of course, there is well known that there are rare conditions characterised by massive reduction of the number on insulin receptors or circulation of high titres of anti-insulin or anti-insulin receptor antibodies.
Insulin has many releasing factors and affecters (glucose, amino acids, NEFA, ketone bodies, gut hormones etc), The feed-back mechanism it is not well explored and there are physiological conditions that insulin resistance is an adaptive mechanism.
For the investigation of insulin resistance syndrome, the cold standard is Hyperinsulinemic euglucemic glucose clamp, but this method is reserved for the study of small number of patients and of course in a hospital basis.
An other, not less detailed approach, is the ' Frequently sampled IV glucose tolerance test', but and this method is not ideal for large studies because it requires obtaining 30 blood samples over 3 hours.
For large studies and for the every day clinical practice we can use the ' Quantitative insulin sensitivity check index' and the ' Homeostasis model assessment'. Both those indexes are well correlated with clamp techniques, mainly QUICKI, and both are easily calculated from a single blood sampling for glucose and insulin.
The whole body insulin sensitivity and action estimated by clamp techniques reflects glucose disposal, mainly by muscles. Adipose tissue accounts only for the 10% of glucose uptake and an other 30% is uptake by the liver.
This fact has led to the extrapolation that whole body insulin resistance starts and occurs in the muscles.
The truth is that insulin resistance is initiated in adipose tissue and a series of events produces resistance and in other organs and tissues.
The main organs affecting insulin resistance states are: adipose tissue, muscles, liver and pancreas.
The main controller is white adipose tissue (WAT): Low expression gene and protein of IRS-1 and GLUT-4. The low glucose uptake by WAT produces insulin resistance in muscle and liver through production of insulin antagonists or by reducing enhancers of insulin action.
Muscle tissue is the 'consumer'. Insulin stimulated glucose uptake and glycogen synthesis are reduced, even with normal IRS-1 protein expression. Increased drainage of NEFA in the liver pushes gluconeogenesis, there is a marked decrease of glycogen synthesis and insulin clearance is reduced. I have to mentioned at this point that in the liver, the mechanisms of insulin action at the sub-receptor level are not yet well known.
In the pancreas, genetic factors determine how the β-cells respond to insulin resistance and whether someone will become diabetic or not.
Hormones and cytokines produced by WAT have wide-ranging effects on food intake, energy expenditure, and carbohydrate and lipid metabolism.
These secreted factors include tumor necrosis factor-alpha (TNFa), interleukin-6, plasminogen activator inhibitor 1, angiotensin II, leptin, acylation stimulating protein (ASP), adiponectin and resistin.
NEFA (non-esterified fatty acids) have a central role in insulin resistance syndrome. Contrary to the classical mechanism of NEFA -induced insulin resistance as proposed by Randle et al in which NEFA exerts their effect through initial inhibition of pyruvate dehydrogenase, Roden et al found that elevation in plasma NEFA concentration caused insulin resistance by inhibition of glucose transport and/or its phosphorylation with a subsequent reduction of glucose oxidation and muscle glycogen synthesis. Recently it has been reported that increased concentrations of plasma NEFA induce insulin resistance in animals through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1-associated phosphatidylinositol (PI) 3-kinase activity. However, it has been reported that chronic exposure of islets of Langerhans to FFA leads to an increase in basal insulin secretion that compensates for peripheral insulin resistance in rats.
It has also been reported that the high levels of portal FFA may eventually result in an enhancement of hepatic triglyceride synthesis, causing hyperlipidemia and insulin resistance.
Beta-cell, just like any other cell in the body, needs energy to live and work. This energy is produced in respiratory chain of mitochondria, the production of ATP, and is used later on for insulin synthesis and secretion.
In obesity, NEFA levels are increased and this increases the expression of UCP2 of mitochondrion. Increase UCP2 bypassed protons produced in respiratory chain for heat production and no for ATP production. This leads to a decreased ratio of ATP to ADP resulting in an energy deficient cell.
Evidence of the predicted negative effect of uncoupling protein 2 on insulin secretion are the findings that increased levels of the protein in isolated pancreatic islet cells decrease ATP levels, reduce closure of glucose-stimulated ATP-sensitive potassium channels, and inhibit glucose-stimulated insulin secretion.
In a recent prospective study in Australia, they found that: subjects at risk showed deterioration in fasting plasma glucose levels due predominantly to a decline in insulin secretion index without major change in insulin resistance index. Importantly, baseline body fatness (especially central adiposity), as well as increase of body weight with time, were the major predictors of the subsequent decline of insulin secretion index and the consequent rise in fasting plasma glucose.