A method for determining insulin sensitivity and glucose absorption

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There is great interest in measuring insulin sensitivity in patients to quantify the improvement in insulin sensitivity achieved with different therapies, identify insulin sensitivity in individuals to provide further insight into their pathophysiology and to determine optimal treatment approaches and identify changes in insulin sensitivity as early markers of disease progression. In addition, there is considerable interest in determining insulin sensitivity in preclinical research, for similar reasons.

Recently, several methods for determining insulin sensitivity from oral glucose tolerance tests (OGTTs) or meal tests have been proposed. One method involves a two-step procedure in which tracers are used to determine the rate of glucose absorption and then the classical minimal model analysis is used to determine insulin sensitivity. The experimental difficulty associated with this method makes it impractical for large studies. Dalla Man et al. (2005a) have developed an approach for simultaneously identifying parameters describing glucose absorption and insulin sensitivity using seven or more blood samples from meal challenges or OGTTs. This method was validated against multiple tracer methods in non-diabetic subjects and results were well correlated with results from hyperinsulinemic clamps. Dalla Man et al. (2005b). However, this method requires at least seven blood samples and there are as many parameters to be identified as data points collected. In addition, sophisticated modeling software is required and there is no guarantee that a unique, optimal solution will be found. Caumo et al. (2000) derived an index of insulin sensitivity by assuming the rate of glucose absorption closely follows the plasma glucose concentrations during a meal and integrating the equations over a period of time long enough to ensure that both glucose concentrations and insulin action have returned to basal values.

Other, more empiric methods, of determining insulin sensitivity from OGTTs have also been proposed. Stumvoll et al. (2000) empirically obtained an insulin sensitivity measure based on glucose and insulin measurements during an OGTT that was correlated with the glucose infusion rate during a hyperinsulinemic clamp. Matsuda et al. (1999) developed a composite insulin sensitivity measure based on both fasting and mean values of glucose and insulin and showed that this measure was correlated with results from a hyperinsulinemic clamp. Hansen et al. (2007) empirically determined measures of insulin sensitivity from OGTT that were correlated with SI measured by IVGTT. Mari et al. (2001) have also developed a measure of insulin sensitivity (OGIS) based on fitting differential equations describing glucose kinetics at a single time point and then empirically determining several unknown quantities in order to match hyperinsulinemic clamp results. Although the OGIS approach was originally model-based, by fitting the differential equation at a single time point, much of the information in the glucose and insulin profiles is ignored. SUMMARY OF THE INVENTION

The present invention encompasses a model-based method for determining insulin sensitivity and glucose absorption from oral glucose tolerance tests or mixed meals. The present invention has several advantages over current methods. The technique requires about four to six blood samples taken over about two to three hours following glucose ingestion and is therefore applicable to large-scale clinical trials. The analysis involves a reduced version of the classical minimal model, a method for describing glucose absorption using only two parameters, and an integral approach enabling the parameters to be obtained using simple algebra. The present method robustly identifies differences in insulin sensitivity in different patient types as well as improvements in insulin sensitivity arising from pharmaceutic therapy. In addition, insulin sensitivity measurements obtained with the present method are highly correlated with results from hyperinsulinemic clamps (r2> 0.8). This method is therefore a practical and robust method for determining insulin sensitivity under physiologic conditions. The present invention encompasses a method of determining insulin sensitivity from an oral glucose tolerance test or mixed meals by measuring blood glucose levels and analyzing the results of the measurement with

-J- = ύ/ \y ■ A " ^ basal ■ 1 basal ) (1) at VG dl, 1

^ J-.- = - ^ _ ( \ χ1L ppllaas. ma - i 1 I)) ( κ2) ' dt where

• G(t) is the plasma glucose concentration in mg/dl

• RcT" (t) is the rate of appearance of exogenous glucose into the plasma (from meals or injections/infusions) in mg/min

• VG is the distribution volume of glucose in dl

• Si is insulin sensitivity in l/min/(μU/ml)

• I,(t) is the interstitial insulin concentration, in μU/ml (In addition to a time delay between plasma and interstitial insulin concentrations, interstitial concentrations are also lower than plasma concentrations, even in steady state conditions; this difference is not accounted for in these equations. Thus, the proper interpretation OfI1(I) is as the actual interstitial insulin concentration at time t multiplied by the ratio of basal plasma insulin/basal interstitial insulin)

• Gbasai is the basal plasma glucose concentration in mg/dl

• hasai is the basal plasma insulin concentration μU/ml

• τ is the time constant associated with transfer of insulin from plasma to interstitial fluid, in min

• /plasma is the plasma insulin concentration, in μU/ml.

The results can be obtained from any number of samples, preferably at least about four to six samples are obtained. Results obtained from four samples are sufficient to determine insulin sensitivity. The results can be obtained during any time period, preferably the time period is of about two to four hours. Results obtained from a two hour time period are sufficient to determine insulin sensitivity. The method can be used to determine the effect of therapy on insulin sensitivity. The therapy can be any known in the art including, without limitation, pharmaceutical, nutritional or behavioral.

The method has numerous applications, for instance, it can be used in preclinical studies to determine the effect of a therapy; as a prognostic to assess a patient's risk of developing a disease or syndrome such as diabetes or metabolic syndrome; to monitor and/or adjust patient treatment; or in conjunction with automated insulin delivery.