DI/cle, a Measure Consisting of Insulin Sensitivity, Secretion, and Clearance, Captures Diabetic States

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Our data also indicate that IGT encompasses the condition

of decreased insulin clearance with a relatively well preserved

DI/cle and glucose set point (Supplementary Appendix 4 (32)),

and that T2DM encompasses that of decreased DI/cle with a

disrupted glucose set point. A modeling study with simulated

data indicated that changes in insulin clearance may affect glu­

cose dynamics even when the normal glucose set point is main­

tained and can constitute a pathway for progression of glucose

intolerance (19). Our study based on mathematical models

and observational data now indicates that the phenomenon

predicted by this previous model can occur in IGT. Our find­

ings are also consistent with those of a previous study indicat­

ing that an increase in insulin secretion is followed by a

decrease in first-pass hepatic insulin clearance when insulin re­

sistance is induced (15).

Despite the apparent analogy of the moving up–falling off

phenomenon, whether the body possesses the ability to reduce

insulin clearance in response to a decline in DI and the poten­

tial physiological mechanism underlying such a response re­

main unknown. However, evidence suggests that changes in

insulin clearance can be a determinant of glucose intolerance

(21, 37). Whereas the direction of causation of decreased insu­

lin clearance and glucose intolerance remains unclear, a clas­

sification based on DI/cle may provide new insight into the

trajectories of glucose intolerance and T2DM.

Although these results were obtained from a limited number of

individuals, the results were validated by several different mathem­

atical models. Moreover, we attempted to estimate DI/cle from a

hyperinsulinemic-euglycemic clamp alone, OGTT, or a fasting

blood test so that the characteristics of DI/cle can be validated

more easily in the future. Whereas we showed that DI/cle estimated

from a hyperinsulinemic-euglycemic clamp test alone was signifi­

cantly correlated with that estimated from the 2 clamps, perform­

ance of even a single clamp is labor-intensive. Moreover, the

correlation between DI/cle estimated from the 2 clamps and that es­

timated from the single clamp was only 0.52, 0.67, or 0.71. It will

therefore be important to develop more accurate and convenient

methods for estimation of DI/cle in order to validate its physiologic­

al relevance and clinical usefulness.

The current study has several limitations. For simplicity, we

considered only insulin sensitivity, insulin secretion, and insu­

lin clearance. However, insulin secretion has basal, firstphase, and second-phase components (38), and both insulin

sensitivity and insulin clearance have hepatic and peripheral

components (3, 22). Saturation of or time-dependent changes

in insulin clearance (6, 22) were not considered. Although the

models used in this study possesses sufficient expressivity to fit

the data from clamp tests (23) and IVGTT (26, 30), and to

conclude the significance of incorporating insulin clearance

in addition to insulin secretion and insulin sensitivity, as

well as a novel perspective on the progression of glucose in­

tolerance with the βGI model, it is important to devise a

more comprehensive measure that encompasses these more in­

tricate effects in the future. Moreover, several better ap­

proaches to evaluation of the hyperbolic relation have also

been presented, and a power function describing the relation

between insulin sensitivity and insulin secretion gives a better

representation (39-41). Given that insulin sensitivity and insu­

lin clearance are correlated (42), the plane representing 1/insu­

lin clearance2 is not necessarily horizontal (Fig. 2E), and the

curve corresponding to DI also departs from a hyperbola

when the plane departs from the horizontal. Therefore, this

study indicates that insulin clearance should be considered

The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 12

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