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Assessment of Insulin Sensitivity from Steady-State and Dynamic Tests

GiovanniPaciniand Andrea Mari

Introduction

Berson & Yalow (1970) defined insulin resistance as 'a state in which greater-than-normal amounts of insulin are required to elicit a quantitatively normal response'. Several books cover all the biological, physiological and pathological aspects of impaired insulin action (e.g. Moller 1993, Reaven & Laws 1999, Krentz 2002, Porte et al. 2003, DeFronzo et al. 2004) and stress its possible role in the development of vascular diseases, which is the major clinical concern. Insulin resistance is also associated directly or indirectly with diabetes and a wide range of other diseases and may arise at any time during the course of life. A correct and reliable quantification of insulin resistance is clearly important for diagnosis, therapy, prognosis, monitoring of the follow-up and the evaluation of drugs.

Even if several factors influence insulin-mediated glucose uptake, such as lipid metabolism, ion transport, inflammatory processes, protein synthesis, endothelial function, gene transcription and so on, insulin remains the main regulator of glucose homeostasis. Thus the major processes controlled by insulin are the stimulation of glucose uptake, mainly by muscles and adipose tissue, and the inhibition of the hepatic glucose production. A schematic representation of the glucose-insulin system is shown in Figure 3.1. Measuring insulin sensitivity means assigning a value to the change of glucose disappearance from blood for a unit change of systemic insulin.

The glucose clamp is considered the gold standard for measuring insulin sensitivity. This technique is discussed in Chapter 4 and has been the subject of several excellent reviews (e.g. Bergman et al. 1985; Ferrannini & Mari 1998; DeFronzo et al. 2004). Direct measurements of uptake and production require the use of tracers (Wolfe 1992) (see Chapter 6). Here, we describe those tests that are simpler than the clamp and which can be performed more easily in a normal clinical setting and, for every test, the methods for its data analysis.

Clinical Diabetes Research: Methods and Techniques Edited by Michael Roden © 2007 John Wiley & Sons, Ltd ISBN 978-0-470-01728-9

Figure 3.1 Schematic representation of the processes involved in glucose homeostasis. Input into the peripheral glucose space (where glucose measurements are performed) can occur from either intravenous injections (IVGTT, Clamp, IST) or oral load (OGTT) and endogenous glucose production (HOMA, QUICKI, IIT). Peripheral insulin (measured variable) either remains at its fasting level (HOMA, QUICKI) or changes because of exogenous infusion/injection (Clamp, ISI, IIT, insulin-modified-FSIGT) or for stimulated endogenous release (OGTT, IVGTT). Insulin action is delayed with respect to plasma concentration. Insulin increases peripheral glucose clearance and inhibits liver glucose output. Models for the assessment of insulin sensitivity (minimal model, OGIS, HOMA) consist of a mathematical representation of these processes with various assumptions and simplifications. All tests base the calculation of insulin sensitivity on evaluation of changes in glucose concentration in relation to peripheral insulin levels.

Figure 3.1 Schematic representation of the processes involved in glucose homeostasis. Input into the peripheral glucose space (where glucose measurements are performed) can occur from either intravenous injections (IVGTT, Clamp, IST) or oral load (OGTT) and endogenous glucose production (HOMA, QUICKI, IIT). Peripheral insulin (measured variable) either remains at its fasting level (HOMA, QUICKI) or changes because of exogenous infusion/injection (Clamp, ISI, IIT, insulin-modified-FSIGT) or for stimulated endogenous release (OGTT, IVGTT). Insulin action is delayed with respect to plasma concentration. Insulin increases peripheral glucose clearance and inhibits liver glucose output. Models for the assessment of insulin sensitivity (minimal model, OGIS, HOMA) consist of a mathematical representation of these processes with various assumptions and simplifications. All tests base the calculation of insulin sensitivity on evaluation of changes in glucose concentration in relation to peripheral insulin levels.

In the following sections, the test descriptions highlight specific protocol features. In addition to the specific test aspects, some general rules apply to all experimental settings. In particular, it is advisable that the subject maintains his/her usual lifestyle during the day(s) preceding the test, but with abstinence from alcohol and tobacco. If the experimental procedure is carried out in an outpatient setting, physical exercise should be avoided (no bicycling nor running to the place of the test) and it is prudent in any case to make the subject rest for some time before starting blood collection.

Insulin sensitivity from steady-state tests

When blood glucose levels are in dynamic equilibrium, the rate at which glucose is endoge-nously produced or exogenously administered is equal to the rate of glucose utilisation, mostly controlled by insulin. In basal conditions, glycaemia depends on the concomitant level of insulin. If glucose and insulin are exogenously given, glucose utilisation increases, production decreases and steady-state glucose is achieved after some time. The levels of glucose and insulin during this new steady-state and the glucose infusion rate reflect the ability of insulin to stimulate glucose uptake i.e. insulin sensitivity. Assessment of insulin sensitivity in steady-state conditions is based on this paradigm. The most common tests are the glucose clamp (described in Chapter 4) and the insulin suppression test. Surrogate measurements of insulin sensitivity can also be obtained in fasting conditions, without any external intervention.

Insulin sensitivity from fasting measurements Rationale

Individual fasting plasma glucose level depends upon a controlled balance between hepatic glucose production (HGP) and glucose utilisation. The liver is responsible for providing 90 % of glucose in the fasting state (Eckberg et al. 1999), which is principally utilised (almost two-thirds) by non-insulin-dependent tissues, primarily the central nervous system (Baron et al. 1985). The insulin-dependent tissues utilising the remaining one-third are mostly skeletal muscles and the liver itself. Insulin therefore regulates HGP and glucose uptake to prevent hyper- or hypo-glycaemia. Elevated fasting levels of glucose or insulin are indicative of insulin resistance.

Protocol

Glucose and insulin concentrations are measured from one to three blood samples, usually collected every 10-15 min in the morning after 8-12-hour fasting.

Data analysis

The most common index of insulin resistance in the fasting state is that arising from the homeostasis model assessment formula (HOMA-R). This index is calculated as:

Gh x Ih HOMA-R = —h-h where Gh and Ih are basal glucose and insulin concentrations and k is a constant to scale HOMA-R so that it has the value of 1 (or 100%) with mean normal basal glucose and insulin. For glucose in mmol/l and insulin in ^U/ml, k = 22.5 (Matthews et al. 1985). k is sometimes omitted.

HOMA derives from a mathematical model of the glucose-insulin homeostatic system (Levy et al. 1998) and the authors themselves advise using the modeling approach (HOMA2, http://www.dtu.ox.ac.uk./homa/) instead of the raw formula (Wallace et al. 2004), although no evidence has been provided of any clear advantages to using HOMA2 (Mari 2006).

Another index of fasting insulin sensitivity is the quantitative insulin sensitivity check index, QUICKI (Katz et al. 2000), which is calculated as:

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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