The Big Diabetes Lie

Abbreviations: CIGMA, continuous infusion of glucose with model assessment; FSIVGTT, frequently sampled intravenous glucose tolerance test; HOMA, homeostatic model assessment; IV, intravenous; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin sensitivity check index.

(the reciprocal of IR). During this test a fixed amount of insulin is infused. A variable rate of glucose infusion is used to keep blood glucose level constant to avoid any effect of counterregulatory hormones on insulin sensitivity. The greater the sensitivity to insulin, the greater is the amount of glucose needed to maintain euglycemia. The amount of infused glucose once a steady state is reached is the main determinant of the test (M value [mg- min—1 • kg body weight1]). Because of its precision in quantitating insulin sensitivity under physiologic conditions of insulinemia and glycemia, and because it can be combined with other methods (eg, tracer glucose infusion, indirect calorimetry), the euglycemic hyperinsulinemic clamp remains the preferred technique to evaluate the contribution of impaired insulin sensitivity to overall glucose homeostasis. Unfortunately, the invasive and complex nature of the test limits its use in epidemiologic studies or clinical practice.

Minimal models: frequently sampled intravenous glucose tolerance test and minimal modeling

Minimal models work by using individual patient data from intravenous glucose tolerance tests, and establishing the profile of both insulin and glucose. Because insulin causes glucose to fall and glucose causes insulin to rise, the feedback loop can be mathematically analyzed to estimate the (-cell function and IR [32].

The frequently sampled intravenous glucose tolerance test is less laborintensive than the euglycemic hyperinsulinemic clamp: there is no need for the continuous adjustment of glucose infusion rates, so bedside glucose readings are not necessary. It is also, however, a time-consuming and expensive test.

The homeostatic model assessment (HOMA) of (-cell function and IR is a method for assessing (-cell function and IR from basal glucose and insulin or C peptide concentrations. It is based on mathematical modeling of the interaction of (-cell function and IR in steady state.

HOMA1, the original model from Matthews and coworkers [33], contained a simple mathematical approximation of the original nonlinear solution to the iterative equations. These equations are simplified to as follows. For IR: HOMA1-IR = (FPI x FPG)/22.5. For (-cell function: HOMA1-%B = (20 x FPI)/ (FPG — 3.5), where FPI is fasting plasma insulin concentration in milliunit per liter and FPG is fasting plasma glucose in millimole per liter.

The group that published these equations later developed a corrected nonlinear computer model (HOMA2) [34]. The computer model can be used to determine insulin sensitivity (%S) and (-cell function (%B) from paired fasting plasma glucose and insulin or C peptide concentrations across a range of 1 to 2200 pmol/L for insulin and 1 to 25 mmol/L for glucose. Because the model was calculated in a steady state situation it should not be used when glucose levels are in the hypoglycemic range or other non-steady-state situations. Also, the model is based on the relationship of IR and (-cell function, so that both estimations should be reported.

It is recommended to use this model when HOMA is compared with other models (HOMA2 model is available from www.OCDEM.ox.ac.uk). The group who designed the model has recently published a review on its use [35].

The quantitative insulin sensitivity check index [36] is similar to the simple equation form of the HOMA model in all comparative respects, except that QUICKI uses a log transform of the insulin x glucose product. It has the same disadvantage and limitations as the use of HOMA: QUICKI = 1/log(FPI) + log(FPG) = 1/([log(FPI x FPG]), where FPG (milligrams per deciliter) is the fasting glucose concentration and FPI (microunit per milliliter) is the fasting insulin concentration.

In the revised QUICKI, to improve the performance of this estimation Perseghin and coworkers [37] included fasting free fatty acids in the calculation. Incorporation of the fasting FFA concentration (FFA, measured in millimole per liter) into QUICKI leads to a revised QUICKI, which is calculated a follows: revised QUICKI = 1/log(FPI) + log(FPG) + log (FFA). The revised equation showed an improvement in its association with insulin sensitivity in healthy, nonobese individuals. This modified index has not been validated in children.

Continuous infusion of glucose with model assessment

Continuous infusion of glucose with model assessment is a steady-state mathematical model, which assesses the glucose and insulin responses to a low-dose glucose infusion. It has not been widely benchmarked, however, and used by only a few groups [38].

Indexes of insulin sensitivity from the oral glucose tolerance test

Although the oral glucose tolerance test is not designed to asses IR, indices of IR have been developed [39-44]. Two of these indices have been validated in children [28].

Clearly, most of these tools are used for research purposes. The HOMA and QUICKI, however, could be quantified from a single fasting glucose and insulin determination and may find application in clinical practice.

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