CAPÍTULO 3: PROPUESTA DE PLANEACIÓN BÁSICA DEL ISR E IVA
3.1. Aplicación de la planeación a la determinación del ISR e IVA
The m etabolic function of insulin includes regulation of processes such as glucose uptake, glycogen synthesis and lipolysis. Insulin is secreted by the pancreatic p cells in response to increased levels of plasm a glucose resulting in glucose u p tak e into fat tissue and m uscle and red u ced hepatic glucose production. Type 2 diabetes is characterised by; resistance to insulin action on glucose u p tak e, im p aired inhibition of hepatic glucose p ro d u c tio n an d dysregulated insulin secretion (Kahn et ah, 1996).
Diabetes Mellitus is the m ost common metabolic disorder w orldw ide. Type 2, or non-insulin dependent diabetes mellitus (NIDDM), accounts for m ore than 90% of cases. Prevalence of type 2 diabetes is affected by environm ental factors such as, diet, physical activity, and age as well as genetic predisposition (Kahn, 1998). M any type 2 diabetics have hyperglycaem ia despite h ig h er th an n o rm al concentrations of plasm a insulin, or hyperinsulinem ia. Initially there is increased insulin secretion to compensate for the decreased sensitivity of target tissues to insulin. Overt diabetes only occurs w hen the pancreatic p cells fail to com pensate for insulin resistance, therefore, hyperinsulinem ia m ay be present in a substantial proportion of the "normal' non-diabetic p o pulation (Reaven, 1996). The fact that insulin resistant persons are able to compensate by secreting en o u g h in su lin to overcom e in su lin resistance does n o t m ean th a t this hyperinsulinem ia is not having any adverse effects in tissues other than fat, liver and muscle.
1.8.1 Syndrom e X, diabetes and coronary heart disease
In hyperinsuliném ie individuals w ho have not yet developed type 2 diabetes th e re is an a sso c ia tio n b e tw e e n in su lin re sista n c e , h y p e rte n s io n , hypertriglyceridem ia / dyslipidem ia and obesity. This cluster of abnormalities w hich predispose to atherosclerosis and cardiovascular diseases are described as "syndrome X' or "the insulin resistance syndrome". Several epidem iological studies have show n that m ortality rates due to coronary artery disease (CAD) are at least doubled in diabetic subjects (Steiner, 1994; Stout, 1993). However, the incidence of CAD in NIDDM is not related to duration of diabetes. A possible explanation for this and the observation of atherosclerosis at the tim e of diagnosis of NIDDM is th at there is increased atherogenesis caused by the com bination of risk factors that m ake up syndrom e X (Steiner, 1994). Some of these risk factors are discussed below.
1.8.2. D yslipidem ia
In d ia b e te s th e m o st co m m o n c h an g e in c irc u la tin g lip id s is hypertriglyceridem ia w hich reflects an increase in the n u m b er of VLDL particles (Ferrannini, 1997). There is evidence that increased levels of VLDL are a risk factor for cardiovascular disease (Mack and Hodis, 1996). Insulin acts to reduce the synthesis of VLDL by the liver and release of TAGs into the circulation. Therefore, insulin resistance-associated hyperinsulinem ia results in e n h a n c e d h e p a tic VLDL s y n th e s is a n d h y p e r tr ig ly c e r id e m ia . H ypertriglyceridem ia has been show n to enhance m onocyte b in d in g to endothelial cells, an im p o rtan t early event in the atherosclerotic process (H oogerbrugge et al., 1996). Lipoprotein lipase is an insulin-regulated enzym e
that regulates the removal of TAG from VLDL which is then degraded to LDL and rem oved from the peripheral circulation. A decrease in insulin action in Type 2 diabetes w ould therefore contribute to increased VLDL levels (Orchard, 1990). Increased levels of VLDL are associated w ith reduced HDL levels, as the breakdow n products of VLDL are assem bled into HDL. A nother explanation for the inverse relationship betw een HDL and TAG concentration relates to the activity of cholesterol ester transfer protein prom oting the m ovem ent of CE from HDL to VLDL. Thus high VLDL levels results in loss of CE from HDL and lower plasm a HDL-cholesterol concentration.
The m ost pow erful predictor of CAD is increases in LDL and LDL is the major supplier of cholesterol to foam cells. The m ortality rate due to CAD a t any given serum cholesterol concentration is approxim ately four tim es greater in those w ith diabetes, however, LDL levels are similar in diabetics to those seen in the general population. This suggests that any given am ount of LDL is more atherogenic in a diabetic. Changes which m ay occur to LDL to m ake it m ore atherogenic include glycation an d oxidation w hich p ro m o te u p tak e by m acrophages (Orchard, 1990) and the presence of sm aller and denser LDL (Steiner, 1997). Analysis of LDL particle size has show n th at persons w ith sm aller LDL (diam eter < 255Â) have higher plasm a TAG concentrations and low er HDL concentrations. Because similar changes in plasm a TG and HDL are associated w ith insulin resistance it seem s likely th at sm all LDL is also associated w ith insulin resistance. A study of 100 norm al persons has show n those w ith small dense LDL were more insulin resistant and glucose intolerant, hyperinsuliném ie, hypertensive, hypertriglyceridem ic and h ad low er HDL
concentrations (Reaven et al., 1993). This suggests that small dense LDL can be ad d ed to the cluster of abnorm alities w hich m ake up syndrom e X (Reaven, 1996).
1.8.3. H ypertension
The prevalence of hypertension is greater in the diabetic p o p u latio n and peripheral vascular disease, aortic calcification and CAD occur m ore commonly in those diabetic patients that also have hypertension (Steiner, 1994; Stern and Tuck, 1996). One reason for this m ay be defects in ion channels as several m em brane ion tran sp o rt system s are altered by insulin, such as the Na,K- ATPase pum p, the Ca^^-ATPase pum p and the Na'^/H'*’ antiporter system (Stern and Tuck, 1996). This results in sodium retention and an increase in cytosolic calcium and grow th of sm ooth muscle cells. Other effects of insulin w hich m ay prom ote vasoconstriction and increase blood pressure are enhanced expression of endothelin-1 in endothelial cells and increased sym pathetic nervous system activity (Reaven, 1996). Reduction in blood pressure has also been reported w ith better glucose control in diabetic subjects, im plying that abnorm alities in both glucose and insulin can m odulate blood pressure (Stem and Tuck, 1996).
1.8.4. H yperinsulinem ia and increased atheroclerosis
Several prospective studies have show n th at hyperinsulinem ia is associated w ith atherosclerosis in the general population (reviewed in, (Steiner, 1994)) and a m ore recent stu d y provides su p p o rt th at endogenous h y p erinsulinem ia increases the risk for CAD in patients w ith type 2 diabetes (Lehto et al., 2000). Clinical observations that IDDM patients w ith low insulin requirem ents show ed
delayed vascular dam age and a higher survival rate than those requiring larger doses also support the idea that insulin is a risk factor for atherosclerosis (Joron and Webb, 1991).
It has already been m entioned that hyperinsulinem ia influences a n u m b er of potentially atherogenic factors such as alterations in lipids and developm ent of hypertension. In addition to this, hyperinsulinem ia is associated w ith increased levels of plasm inogen activator inhibitor 1 (PAl-1). Fibrin is deposited in the occlusion of coronary arteries and m ay contribute to p laq u e g ro w th by stim ulation of cell proliferation and by the binding and accum ulation of low- density lipoprotein (Juhan-Vague et al., 1991). PAl-1 is a physiological inhibitor of fibrinolysis and increased PAl-1 w ould therefore result in decreased rem oval of fib rin (Stout, 1993). Elevated PAl-1 is found in p a tien ts w ith CAD, hypertension, obesity and hypertriglyceridem ia suggesting an association w ith insulin resistance and hyperinsulinemia. To further support this, treatm ent w ith anti-diabetic drugs have show n parallel reductions in insulin and PAl-1 levels (Juhan-Vague et al., 1991). At physiological concentrations insulin stim ulates the p ro liferatio n and m igration of cultured arterial sm ooth m uscle cells, and cholesterol synthesis and LDL b inding in bo th sm ooth m uscle cells an d m o n o cy te m acrophages (Stout, 1990). These m u ltip le effects of in su lin (sum m arised in table 3.) w ould be expected to contribute to lesion form ation an d su g g est a p o ten tial d irect role of in su lin in the d e v e lo p m e n t of atherosclerosis.
Table 3 Effects o f insulin on arterial tissue
(2) increased formation of lipid lesions (Abe et al., 1996; Stout, 1970) • increased lipid synthesis (Stout, 1970)
• connective tissue synthesis (Abe et al., 1996)
• proliferation and m igration of arterial sm ooth m uscle cells (Larson and Haudenschild, 1988; Pfeifle and Ditschuneit, 1981)
• increased cholesterol synthesis and LDL binding in sm ooth m uscle cell and monocyte derived macrophages (Krone and Greten, 1984; Krone et al., 1988)
1.8.5. H yperglycaem ia
Im paired glucose tolerance (IGT), a category that falls betw een norm al glucose tolerance and diabetes, can be experienced for years before overt diabetes and hyperglycaem ia develop. Nondiabetic subjects w ith IGT have about a twofold increase in the risk of m acrovascular disease. The risk starts at levels of glycaemia considerably lower than the threshold for the diagnosis of diabetes (Bonora et al., 2000; Laakso, 1999).
O ne m echanism by w hich glucose m ay influence atherosclerosis is the form ation of advanced glycation end p ro d u cts (AGEs), d u e to pro lo n g ed incubation of proteins w ith glucose. In its open chain form glucose has an a ld eh y d e g ro u p th a t reacts w ith lysine resid u es of p ro te in s fo rm in g fructoselysine, The am adori product'. A protein w ith the am adori p roduct can be cross-linked to other proteins and lipoproteins through its' reactive carbonyl
group (Semenkovich and Heinecke, 1997) (see figure 1.7). These AGEs are thought to prom ote vascular disease.
Glycation of apolipoproteins in all classes of circulating lipoproteins has been found in diabetes. G lycated LDL interacts poorly w ith the LDL receptor, therefore its residence time in the plasm a and in the extracellular space of the artery wall, where oxidative modification can occur, is increased . M acrophage scavenger receptors recognise proteins m odified by AGEs and m ediate their uptake and degradation, and thus, m ay take u p AGE m odified LDL at an increased rate. This process has been show n to stimulate the release
Figure 1.8
Set o f reactions which glycated proteins m ay undergo:Dicarbonyls covalently modify proteins and prom ote cross-linking reactions and reduced oxygen species trigger the oxidation of proteins and lipids
C H = 0 C H - O H C H = 0 I II I C H - O H ^ C H - O H --- ► C = O I I I R R ^ \ R (G lu co se ) Q .. (D icarb on yl) H 2 O 2 HO
I
O xid ation Protein
of cytokines and g ro w th factors (Vlassara et al., 1988). The m acro p h ag e scavenger receptor-m ediated endocytotic uptake of AGEs can be accelerated by insulin th ro u g h a PI 3-kinase d ependent pathw ay (Sano et al., 1998). Also, glycated HDL shows im paired ability to stim ulate cholesterol efflux from cells (Chait and Brunzell, 1996). All of these effects of glycation m ay play a role in increased atherogenesis. Also the reactive oxygen species, superoxide, hydrogen peroxide and hydroxyl radical produced d u rin g glucose autooxidation (see figure 1.7) w ill contribute to lipoprotein oxidation and foam cell form ation. H yperglycem ia has also been show n to prom ote leukocyte adhesion to the endothelium through upregulation of the expression of cell surface adhesive proteins (Morigi et al., 1998). Again, this process is an im portant early event in atherosclerosis.
G lucose-induced activation of PKC m ay represent another pro-atherogenic m echanism . Cells tran sp o rt excess glucose in tracellu larly u sin g glucose transporters, w here it is m etabolised and alters signal transduction pathw ays, such as the activation of diacylglycerol (DAG) and protein kinase C (PKC). DAG contents have been show n to be increased in vascular cells w hen glucose levels w ere increased from 5 to 2 2 m m o l/l. DAG, which activates PKC can be derived from phosphoinositides (Pis) or from the hydrolysis of phosphatidylcholine (PC) by phospholipase C (PLC) or D (PLD). How ever, studies using labelled glucose have show n that glucose is incorporated into the glycerol backbone of DAG, suggesting that the source of glucose-induced DAG appears to be from the de novo pathw ay (Xia et al., 1994).
As m entioned earlier, glucose can affect blood flow and prom ote hypertension. PKC activation has been show n to increase the expression of endothelin-1, a potent vasoconstrictor (Koya and King, 1998) and decrease the p roduction of NO, a potent vasodilator, and its second messenger, cGMP (Craven et al., 1994). Hyperglycaem ia, like hyperinsulinem ia, also reduces Na^/K^-ATPase activity, which affects cellular functions such as contractility, grow th and differentiation (Xia et al., 1995).
1.8.6. O besity
Two major types of obesity can be easily defined. These are u p p er body (apple) and low er body (Pear) obesity. U pper body, fat distribution is m easured as increased w aist to hip ratio, and is associated w ith hypertriglyceridem ia, low HDL-cholesterol levels, im paired glucose tolerance and an increased risk of diabetes and atherosclerosis (Stout, 1993). Insulin concentrations, bo th in the basal state and after a glucose challenge are associated w ith increasing body w eight and are reduced by w eight loss. U pper body obesity is associated w ith large fat cells, w hich tend to be insulin resistant, suggesting disturbances in abdom inal fat lipolysis (Klannemark et al., 1998).
The following m odel has been proposed to explain the m echanism of obesity- associated cardiovascular disease:
Initially increased intra-abdom inal fat leads to increases in circulating free fatty acids, accompanied by the developm ent of insulin resistance. This com bination increases the secretion of VLDL from the liver and hepatic lipase activity
resulting in the dyslipidem ia of central obesity; hypertriglyceridem ia, w ith the generation of small dense LDL and reduced HDL cholesterol. In addition to this change in lip id profile, im paired glucose tolerance develops from insulin resistance, leading to hyperglycaemia. Finally increased arterial blood pressure accelerates atherogenesis further (Schwartz and Brunzell, 1997).
F ig u r e 1.9 Diagram illustrating some o f the factors involved in the insulin resistance syndrom e th a t m ight account fo r the observed increase in
atherosclerosis Genetics Upper Body Obesity