Requerimientos necesarios para el cálculo de los valores de épsilon

Central obesity was first described as an adverse health factor in the early 1950’s (273) and later confirmed by numerous studies (274-276). The availability o f CT scanning then allowed looking at the impact o f intra-abdominal fat collection separately from

other components o f the insulin resistance syndrome (277). Reduction o f intra-abdominal fat by caloric restriction or exercise ameliorates the insulin resistance and other

components o f the insulin resistance syndrome (278). The cause o f increased

cardiovascular risk in obesity is likely to be multifactorial. The abnormal lipid profile as well as the hypertension, insulin resistance and coagulation defects often occurring with obesity could also each be contributing to the increased cardiovascular risk.

1.2.7.1.7. Coagulation factors as a cardiovascular risk factor

Several coagulation factors have been associated with an increased cardiovascular risk. O f these three have been reported to be associated with insulin resistance: PAI-1 (279;280), fibrinogen (281;282), and von W illebrand-factor (56;281;283).

1.2.7.1.8. The effect o f a combination of different components of the insulin resistance syndrome on cardiovascular risk

Thus there is evidence that most if not all o f the components o f the insulin resistance syndrome are associated with an increased cardiovascular risk. Data from the Whitehall II study, estimating insulin resistance from the results o f an oral glucose tolerance test, suggests that the increased prevalence o f the insulin resistance syndrome may contribute to the higher coronary risk found in individuals belonging to lower socio-economic groups (284). It is important to know which component(s) is/are the most dangerous.

In the Caerphilly and Speedwell studies Yamell et al. looked at the concepts o f the insulin resistance syndrome in two prospective cohorts o f white men. In three different models o f metabolic syndrome no predictive value for cardiovascular disease was found after adjustment for conventional and metabolic risk factors. The study did not detect any complex relation among the five variables defining the insulin resistance syndrome. Thus the excess cardiovascular risk found in certain subjects was no greater than can be

explained by individual effects o f the defining variables in a multiple logistic model. There was also no evidence o f clustering o f the single components o f the insulin resistance syndrome in these cohorts (67).

Epidemiologists have pointed out the methodological difficulties in ‘factoring out’ the relative risks from individual risk factors when those risk factors are themselves highly inter-eorrelated (285). Thus most studies examining the influence o f individual

components o f the insulin resistance syndrome are difficult to interpret, as (by definition o f this syndrome) several putative cardiovascular risk factors occur simultaneously.

A related question is whether agents that improve multiple components o f the insulin resistance syndrome are more beneficial on cardiovascular risk than those that affect only a single component. For example metformin (which improves several components o f the syndrome) (286-288) was superior to insulin (which improves only glucose tolerance) in the obese subgroup o f the UKPDS (241). Metformin decreased cardiovascular risk to a substantially greater degree than could be explained on the basis o f an improved glyeaemie control. However the parallel Hypertension in Diabetes Study gave no

indication that ACE-inhibitors (which improve several components o f the syndrome) are superior to beta-blockers (which improve only blood pressure and may even increase insulin resistance) (272). At present we have relatively few such data and therefore can not say whether agents influencing several components are generally superior to more focussed treatments.

If the increased cardiovascular risk o f the insulin resistance syndrome is the consequence o f an antecedent (e.g. NEFA, circulating cytokines or endothelial dysfunction) then treating the insulin resistance itself may have little or no impact on cardiovascular risk.

1.2.7.2.The insulin resistance syndrome and type 2 diabetes mellitus

A num ber o f studies have examined the relationship between the insulin resistanee syndrome and the incidence o f subsequent type 2 diabetes mellitus (62). It has been shown that the insulin resistance syndrome (with insulin resistance, hyperinsulinaemia, dyslipidaemia and hypertension) can antedate diabetes by several years and thus, perhaps contribute to the cardiovascular risk in the prediabetic patient (289). Both insulin

(290). In Pim a Indians insulin resistance was found to be a major risk factor for the development o f diabetes, predicting two thirds o f the cases o f diabetes (7). Only one third was predicted by a reduced insulin response. However, insulin resistance was not found to be an universal concomitant o f diabetes in all epidemiological studies: In a small group o f black patients with type 2 diabetes only 50% o f those studied were insulin resistant (291), suggesting a heterogeneity o f aetiology, particularly apparent in different ethnic groups.

Himsworth was the first to suggest that type 2 diabetic patients could be divided into ‘insulin sensitive’ and ‘insulin resistant’ on the basis o f the ability to dispose o f an oral glucose load by exogenous insulin (292). Subsequently a large number o f studies reported that plasm a insulin levels during an oral or intravenous load in patients with type 2

diabetes were normal or higher than normal, concluding that tissue insensitivity to insulin plays an important role in the glucose intolerance (27;29;293). Alford documented a blunted decline in plasma glucose concentration following intravenous insulin in type 2 diabetic patients with fasting hyperglycaemia (294). Human forearm perfusion technique studies have also shown an impairment in insulin mediated glucose uptake in type 2 diabetes (22-24). Using the quadruple infusion technique (co-infusion o f epinephrine and propranolol to suppress endogenous insulin production, glucose and insulin) Reaven et al. demonstrated that diabetic patients manifest insulin resistance (25-29).

In Type 1 diabetes, those with least insulin resistance are reported to have the best cardiovascular prognosis (295). The same may also apply in type 2 diabetes (296). In diabetic subjects it is not usually clear whether insulin resistance is detrimental above and beyond the impaired glucose tolerance that it induces. Thus, review o f records from the A berdeen diabetic clinic demonstrated that weight loss in type 2 diabetes was

advantageous in terms o f improved life expectancy. This study could not distinguish whether better glyeaemie control or improved insulin resistance was the reason for the benefit (297). Recently, the UKPDS implied that metformin as a first line treatment in

overweight diabetic patients produced a better cardiovascular outcome than sulphonylureas or insulin despite equivalent glyeaemie control (241).

Analysis o f the Paris Prospective Study suggests that a high plasma NEFA concentration is a risk m arker for deterioration o f glucose tolerance independent o f the insulin

resistance or the insulin secretion defect that characterizes subjects at risk for type 2 diabetes (298). This might suggest that abnormal NEFA metabolism antedates insulin resistance or/ and the development o f diabetes.

Three lines o f evidence have been used to promote insulin resistance rather than insulin deficiency as the primary defect leading to the development o f type 2 diabetes (as

opposed to being secondary to hyperglycaemia). Firstly, insulin resistance has (at least in some populations) an inherited component (299;300). Secondly, some studies have pointed to abnormal insulin action but normal insulin secretion in patients at high risk o f developing type 2 diabetes before hyperglycaemia ensues (301;302). However, it is not easy to define strictly normal insulin secretion, and subtle abnormalities such as loss o f normal pulsatile insulin release have been identified in subjects with impaired glucose tolerance (303). Thirdly, insulin resistant subjects progress from normal glucose tolerance to diabetes more rapidly than their insulin sensitive counterparts (304;305).

To conclude it thus appears overwhelmingly likely that, at the minimum, insulin resistance causes diabetes to become clinically overt earlier than it would otherwise. Indeed there may be a large number o f patients in whom reduction in insulin resistance may delay, prevent or reverse diabetes. Such delay, prevention or reversal o f diabetes has been achieved by weight loss. Therapeutic agents which reduce insulin resistance might have the same benefits, so that a legitimate aim o f treatment might be to delay or prevent diabetes mellitus in susceptible patients. In subjects already diabetic, there may be

additional benefits to reducing insulin resistance in regard to long-term outcome. It would appear that the prognosis o f Type 2 diabetic subjects is less determined by their

glyeaemie eontrol than whether they show other features o f the insulin resistanee syndrome in addition to hyperglyeaemia (306).