Beta-Cell function and glucose homeostasis
Insulin secretion, together with the sensitivity to insulin of glucose-utilizing tissues, is a key player in glucose homeostasis. What is relevant for glucose homeostasis is not the absolute insulin secretion levels but insulin secretion relative to glucose, as typically assessed by the β-cell dose-response during the physiologic condition of oral glucose ingestion (Figure 8.3). Thus, β-cell glucose sensitivity is strongly inversely associated to mean glucose levels during a standard OGTT and explains, together with insulin sensitivity, a substantial proportion of the variability in glucose levels [31,99].
It should be recalled that two distinct mechanisms determine glucose sensitivity: the ability of the β cell to respond to intravenous glucose and the incretin effect. Both these mechanisms contribute to glucose homeostasis in a significant manner [38,161].
The different modes of response of the β cell exert a specific role in the regulation of glucose levels. One important aspect is the control of fasting glucose levels, which is achieved by a modulation of fasting insulin secretion. In healthy subjects, insulin resistance does not produce relative fasting hyperglycemia, as the fasting secretory tone is properly upregulated, to the extent that fasting glucose is not related to insulin sensitivity . Notably, upregulation of fasting secretion occurs through an upward shift of the β-cell dose-response, induced by insulin resistance. This mechanism is specific for the basal condition, as it does not affect the dose-response slope, that is, glucose sensitivity .
The role of the early secretion mechanisms is more difficult to ascertain.The ability of the normal β cell to anticipate the secretory response is reputed to provide a “priming” mechanism that compensates for the relatively slow action of insulin in muscle, or possibly restrains glucose production more efficiently . Indeed, the estimate of early secretion obtained by modeling analysis has been shown to be related to glucose levels . A more direct proof of the relevance of an anticipated secretory response comes from a study evaluating the effects on glucose levels of two insulin profiles with the same mean value but different timing: the anticipated profile produces lower glucose than the delayed one .
Potentiation phenomena also have a role in glucose tolerance. Enhancement of insulin secretion at the end of an OGTT compared to the beginning has been shown to be related to 2-h glucose [31,164]. It is also likely that the potentiation phenomena observed during the 24 hours contribute to a more efficient control of glucose tolerance.
The β cell is an extraordinary organ. Only one gram of tissue exerts a function that is fundamental for living. The β-cell response exhibits a high degree of sophistication and can finely tune insulin secretion to cope with the metabolic needs. Appropriate control of glucose levels, indispensable for healthy living, is almost entirely ensured by this small but powerful organ. β-Cell dysfunction may therefore easily result in alterations to the multiple biologic action of the hormone. As discussed in depth in Chapter 24, β-cell dysfunction is a key feature of diabetes. Comprehension of the mechanisms controlling such a fine and articulated function is not straightforward, but gaining an understanding of the as yet unresolved questions in order to pave the way for new and more effective cures for this widespread disease is of prime importance.