Beta cell function and its relation to insulin action in humans: a critical appraisal

The importance of both insulin resistance and beta cell dysfunction in the pathogenesis of glucose intolerance is widely recognised. Also popular is the concept that beta cell secretory function must be viewed in the context of extant insulin resistance. This For Debate moves from the premise that, whilst insulin action in vivo can be measured directly by a variety of essentially coherent techniques, measurement of beta cell function is more problematic. We therefore concisely survey the principal in vivo techniques that explore the diverse aspects of beta cell function and conclude that: (i) inter-correlation of clinical tests is only modest in non-diabetic subjects and poor in diabetic individuals; (ii) no single clinical test allows beta cell function to be assessed with accuracy and specificity comparable to those of insulin sensitivity; and (iii) short of complex experiments, mathematical modelling is necessary to interpret insulin secretory responses. Next we discuss the hyperbola paradigm used to describe the reciprocal relation of beta cell function to insulin sensitivity and suggest that: (i) insulin responses reflecting the basal beta cell tone are indeed inversely related to insulin action across degrees of glucose intolerance; (ii) modes of beta cell function that selectively reflect the dynamic response to acutely changing glucose concentrations are largely independent of insulin action; and (iii) when measured by experiment or resolved by modelling, quantitatively the most important of these dynamic secretion parameters is the glucose dose-response curve (glucose sensitivity). In fact, glucose excursions following glucose ingestion (i.e. glucose tolerance) are best explained by dynamic parameters of beta cell function.