explained by higher -cell sensitivity during the meal, which may
lead to lower glucose excursions.45
Severalfactors may contribute to differences in insulin secretion
following an MTT compared with the OGTT. The MTT has a lower
glycemic index than the OGTT, which may lead to lower glucose
excursions.46 Moreover, slower gastric emptying following theMTT
due to larger volume,47 solid character,48 and fat content49 will lead
to a slower entry of nutrients into the circulation.
The MTT might be considered as an additional tool for the
assessment of metabolic abnormalities, in glucose-intolerant and
insulin-resistant states.34
Thus, the MTT is a more physiological test than the OGTT, in
regard to human diet, and is potentially able to give useful information
concerning islet -cell function in the different categories
of glucose intolerance,50 but not insulin sensitivity/resistance per
se.
36
As any other method that measures glucose tolerance, the MTT
does not assess insulin sensitivity directly and may not be repeated
in the same subject or animal on the same day.
Rapid Insulin Sensitivity Test
A new method for insulin sensitivity quantification, called the
Rapid Insulin Sensitivity Test (RIST), was described and evaluated
for use in rats,51,52 cats53,54 mice55 and humans.56 The standard
dynamic profile for the RIST in fed and fasted humans as well as
the RIST insulin sensitivity index is shown in Fig. 2.
The RIST is an euglycemic test and is carried out after establishing
the glycemic baseline, which is done by taking arterialized
venous blood samples at 5 min intervals until three consecutive
measurements are stable. An insulin infusion is commenced
(50 mIU/kg administered over 5 min) and, after 1 min, glucose
samples are taken at 2 min intervals, and glucose is infused intravenously
at a variable rate to maintain euglycemia. The test is
completed when no more glucose is required. At the standard test
dose of insulin of 50 mIU/kg, the RIST in the fasted state is complete
within approximately 40 min. The RIST index, the insulin
sensitivity parameter, is simply the amount of glucose that had to
be administered in order to maintain euglycemia after the bolus
administration of insulin.52
The majority of the insulin sensitivity tests are done in the
fasted state, when insulin sensitivity would be logically anticipated
to be at its lowest level. Studies performed by Patarrão
et al. and Lautt et al. indicated that the fasted state results in a
very low insulin responsiveness. It is reasonable that insulin sensitivity
should be under a regulatory mechanism such that in the
fasted state insulin effect would be minimized, and inappropriate
release of insulin would not, therefore, lead to life-threatening
hypoglycemia. The RIST can be carried out in the fed state.9,56 Furthermore,the
RIST allows insulin sensitivity assessment before and
after a meal, making it possible to test both meal and drug effects
on insulin sensitivity.56,57
The RIST is extremely sensitive and can be shown to generate
dose-response relationships to insulin, which makes the RIST the
most advantageous method in the determination of small differences
in insulin sensitivity. This method is able to be carried out
more than one time in the same subject with high reproducibility,
and is sufficiently versatile to permit paired experimental designs,
in the same subjects and on the same day. Both the accuracy and
precision of the test can be assessed from determination of the
deviation from the ideal euglycemic target.52
Insulin release normally occurs in a pulsatile manner, and
hormones released in a pulsatile manner are best studied by pulsatile
administration.58 Based on this assumption, the intravenous
insulin bolus administered at the beginning of the RIST mimics the
physiological insulin action. It also avoids the vagal withdrawal
and sympathetic activation induced by sustained hyperinsulinemia,
during the HIEC55,59 and the hypoglycemia caused by the
acute ITT.59 It does not alter levels of counter-regulatory hormones,
such as catecholamines, somatostatin or glucagon.54 Moreover,
both insulinemia and glycemia return to basal levels after each
RIST.
One methodological issue relates to the basal glucose concentration
determined before and after the RIST. Previous studies
demonstrate clearly that there is no mean change in basal blood
glucose levels used as the euglycemic target when, for example,
compared before and after denervation of the hepatic plexus in
rats60 or atropine.61 In addition, we have also determined thatthere
is no correlation between the magnitude of the RIST index and
basal glucose levels when compared using a large number of data
points.52 Of more concern is the importance that glucose uptake
or output should not change during the RIST. Whatever stimulus
is used, including either ablation or stimulation protocols, the
stimulus is administered prior to conducting the RIST, and a new
stable glycemic baseline must be demonstrated. In addition, at the
conclusion of the RIST index, the re-established baseline must not
be significantly altered. In the event that such alteration occurs, it
suggests that glucose output either increased or decreased during
the test. This is usually obvious by comparing the shape of normal
RIST curves with that obtained in the presence of the altered baseline.
In such situations, the data must be excluded, and the RIST
repeated.
None of the available methods available to estimate insulin sensitivity/resistance
proved to be a reliable way to assess insulin
sensitivity/resistance since most of them have non-physiological
continuous infusion of insulin and/or glucose, which interfere with
peripheral insulin sensitivity/resistance; take a long time to be
performed; could not avoid counter-regulatory responses to the
hypoglycemia that follows an insulin bolus; could not allow
the assessment of insulin sensitivity in different conditions in the
same subject, and in the same day; and they only evaluate insulin
sensitivity/resistance in the fasted state. Based on all ofthese drawbacks,
it was necessary to develop another method for assessing
insulin sensitivity/resistance.
To summarize, the RIST is a quick method to evaluate insulin
sensitivity, reproducible in the same subject and on the same day,
utilizes a bolus of insulin to mimic pulsatile insulin release, and can
be performed in the fed or fasting state. In addition, since the RIST
is an euglycemic test, avoids hypoglycemia and prevents the activation
of counter-regulatory hormones. The RIST provides a new
powerful tool to dissect insulin action in the fasted and fed state,
and may provide a means to detect the pre-diabetic state, where
early insulin resistance can be detected well before the impairment
of the direct effect of insulin at a time when lifestyle interventions
can be readily tested.
Simple surrogate indexes for insulin sensitivity/resistance
Homeostasis Model Assessment
The Homeostasis Model Assessment (HOMA), developed in
1985, is a model of interactions between glucose and insulin
dynamics, that is then used to predict fasting steady-state glucose
and insulin concentrations, for a wide range of possible combinations
ofinsulin resistance and -cellfunction.62 Themodel assumes
a feedback loop between the liver and -cell62,63; and glucose concentrations
are regulated by insulin-dependent hepatic glucose
production, while insulin levels depend on the pancreatic -cell
response to glucose concentrations. Thus, a diminished response
to glucose-stimulated insulin secretion reflects deficient -cell
function. Likewise, insulin resistance is reflected by diminished
suppressive effect of insulin on hepatic glucose production.