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

Abstract

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. Abbreviations: AIR, acute insulin response · DI, disposition index · GLP-1, glucagon-like peptide-1 · ISR, insulin secretion rate · M, whole-body insulin-mediated glucose uptake · MCR, metabolic clearance rate Diabetologia (2004) 47:943-956

Restoration of normal glucose tolerance in severely obese patients after bilio-pancreatic diversion: role of insulin sensitivity and beta cell function

“…Our results show that those obese subjects who are IGT or have type 2 diabetes prior to surgery are characterised by impairment of beta cell glucose sensitivity. This result confirms previous findings that impaired beta cell glucose sensitivity is the main determinant of IGT and type 2 diabetes, rate sensitivity and potentiation being relatively minor factors [17][18][19]. The impairment in beta cell glucose sensitivity was seen together with a variable degree of insulin resistance and the attendant upregulation of insulin secretion (Fig.…”

“…As expected from previous work [17][18][19], we found a strong inverse relationship between beta cell glucose sensitivity and glucose tolerance (as the 2-h plasma glucose concentration). This relationship was maintained after surgery, but became significantly steeper (Fig.…”

“…The impairment in beta cell glucose sensitivity was seen together with a variable degree of insulin resistance and the attendant upregulation of insulin secretion (Fig. 3), as described previously [19]. After surgery, insulin sensitivity and insulin secretion showed reciprocal changes, as shown in Fig.…”

“…This could be due to the insufficient power of the OGTT to detect changes in acute insulin secretion [21], as also indicated by the large variability of the rate sensitivity parameter (Table 2) and its modest reproducibility [16], or to the intrinsic differences between the i.v. glucose test and the OGTT [19].…”

The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients

“…Type 2 diabetes mellitus is the most common form of this disease (about 90% of all cases) and it is characterised by reduced insulin action and insulin deficiency [1,4,5]. Insulin resistance in peripheral tissues represents a serious and chronic challenge to the capacity of beta cells to produce and secrete insulin, and normoglycaemia is maintained as long as beta cells can compensate for insulin resistance.…”