Background

Under physiological conditions, insulin sensitivity and beta cell function adapt to each other over a prolonged period^[1]. This means that in cases of ‘healthy’ obesity, i.e. without diabetes mellitus, beta cell mass increases as insulin sensitivity decreases (i.e. insulin resistance increases). Conversely, beta cell function decreases in conditions of high insulin sensitivity (e.g., in prolonged starvation). This long-term adaptation of glandular mass to demand is a general principle in endocrinology, which is referred to as dynamic compensation.

The relationship between insulin sensitivity and beta-cell function is hyperbolic in a ‘metabolically healthy’ organism. Via dynamic compensation, beta-cell mass increases with progressive insulin resistance, whereas the disposition index, which is the product of insulin sensitivity and beta-cell function (green line), remains constant (transition from A to B). If this does not happen or is insufficient (transition from A to C), the result is prediabetes or type 2 diabetes mellitus.

The disposition index, which is the product of insulin sensitivity and beta-cell function, remains constant in healthy organisms despite variations in body composition and insulin resistance. If, however, the pancreatic beta cells are no longer able to compensate for increasing insulin resistance by increased cell mass, the disposition index decreases and glucose homeostasis is impaired. This is the case in advanced metabolic syndrome. Depending on the extent of the reduction in the disposition index, prediabetes or type 2 diabetes mellitus may develop.

How to Determine the Disposition Index

For determining the disposition index, data on insulin sensitivity and beta-cell function have to be obtained. This can be done in various ways:

• via a glucose clamp investigation
• via a frequently-sampled intravenous glucose tolerance test (fsIGT)
• an oral glucose tolerance test with a narrow temporal grid of measurement (‘frequently-sampled oral glucose tolerance test’, fsOGT) or
• based on fasting concentrations for glucose and insulin (SPINA Carb).

Calculation

Glucose Clamp

If based on a glucose clamp investigation, the disposition index is calculated as the product of the insulin response curve (AUC_ΔInsulin) and the insulin sensitivity index (ISI_Clamp) with

^[2]

ISI_Clamp is the ratio of the mean glucose infusion rate and the mean insulin concentration during the clamp:

Intravenous Glucose Tolerance Test

Using the fsIGT, the time series of insulin and glucose concentration are to be fitted to the minimal model. Then the disposition index can be calculated with

from the first phase of the insulin response (φ₁) and the insulin sensitivity index (S₁)^[3].

Oral Glucose Tolerance Test

If the fsOGT is used, it is to be coupled with the approach of Matsuda and DeFronzo. Then, the disposition index can be calculated with

from the insulinogenic index (IGI) and the insulin sensitivity index (ISI_composite)^[4].

SPINA Carb

This method delivers a static disposition index that requires fasting concentrations of insulin and glucose only. It is calculated with

as the product of the secretory capacits of pancreatic beta cells (SPINA-G_Beta) and the reconstructed insulin receptor gain (SPINA-G_R)^[5][6].

Interpretation

The approaches presented provide similar but slightly different information. Even though the results of the four methods correlate significantly with each other, several biological factors may cause certain deviations. These are rooted, for example, in the different mechanisms that determine static and dynamic insulin secretion patterns. In a comparative study, the discriminatory power of the static disposition index for the diagnosis of diabetes mellitus was higher than that of the oGTT-based disposition index according to Matsuda and DeFronzo.

Prognostic aspects

A reduced disposition index predicts the evolution of type 2 diabetes^[7]. It is also reduced in certain chronic and inflammatory conditions, including cystic fibrosis^[8], reduced PCSK9 expression^[9] and hidradenitis suppurativa (aka acne inversa)^[10].

In a prospective evaluation of the NHANES study, a reduced static disposition index (SPINA-DI) predicted all-cause mortality over 10 years^[11].