Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods

Abstract

Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic β-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action.

Figure 1

(a) Oral minimal model (OMM). (b) ‘Hot’ or labelled oral minimal model (OMM*). G, total plasma glucose concentration; G_meal, glucose coming from the meal; Ra_meal, rate of appearance of G_meal; Rd, rate of glucose disappearance; Rd_meal, rate of disappearance of G_meal; X and X*, insulin action on glucose disposal and production; NHGB, net hepatic glucose balance [24].

Figure 2

A mixed meal containing [1-¹³C] glucose was ingested at time 0 (a). A primed-continuous infusion of [6,6 ²H₂] glucose was started at time −120 min and then varied from time 0 onward to mimic the anticipated pattern of change of endogenous glucose production (b). An intravenous infusion of [6-³H] glucose was started at time 0, and the rate varied to mimic the anticipated pattern of appearance of the ingested glucose (c) [29].

Figure 3

Different hyperbolas representing the disposition index: a normal subject reacts to impaired insulin sensitivity by increasing β-cell responsivity (state II), whereas a subject with impaired tolerance does not (state 2). In state II, β-cell responsivity is increased, but the disposition index β-cell metric is normal; whereas in state 2, β-cell responsivity is normal, but the disposition index is impaired [38].