6 Insulin sensitivity in the intact organism

Summary Insulin resistance is a classic characteristic of type II diabetes. Precise quantification of insulin sensitivity in vivo is essential for elucidation of the pathogenesis of observed glucose intolerance. The euglycaemic glucose clamp of Andres and colleagues assesses insulin action by disrupting the negative feedback relationship of glucose and insulin. Insulin is infused, but euglycaemia is maintained by exogenous glucose infusion (GINF). At steady state, GINF ( M ) represents total insulin action, i.e. suppression of hepatic glucose output (HGO) plus acceleration of peripheral uptake ( R d ). Coupled with the isotope dilution techniques of Steele et al, these hepatic and peripheral effects can be partitioned, although this approach may underestimate HGO and R d . Modifications of the Steele method may be required for more reliable quantification of glucose turnover. The dose-response relationship between insulin and R d also provides a measure of sensitivity from the glucose clamp: the ED 50 (and R dmax ), analogous to the K m and V max of Michaelis—Menten analysis. However, extensive labour requirements, cost and difficulties in ED 50 estimation limit its widespread use. Glucose clearance ( R d / G ) has also been used to assess insulin sensitivity in subjects of differing glycaemia, but because it fails to rise in proportion to glucose it is an inappropriate measure. Hence, we have introduced the insulin sensitivity index S IP(clamp) , defined as the action of insulin to increase glucose clearance (Δ R d /( G Δ I )), which is independent of prevailing glycaemia and insulinaemia. Lastly, we proposed the minimal model method, which determines insulin sensitivity ( S I ) from analysis of the simple intravenous glucose tolerance test (IVGTT). By adding tolbutamide injection after glucose, the resultant model-based S I is equivalent to S IP(clamp) . Furthermore, minimal model analysis will also yield S G , the parameter of insulin-independent glucose disappearance. We conclude that assessment of insulin sensitivity, whilst important, must be considered in the context of its relation to pancreatic function and insulin-dependent glucose disappearance. Only a clear understanding of the complex interrelation of these factors will lead to elucidation of the mechanisms underlying glucose intolerance.