Insulin response second-phase

If beta cells are incubated in media containing 2 mM glucose and then treated with forskolin and/or tolbutamide, there is a small transient increase in insulin secretion. The subsequent addition of CCK8S leads to a very marked first phase of insulin secretion, but causes no sustained increase or second phase of insulin secretion. These results mean that an increase in cAMP alters the Ca2+ sensitivity of the response elements underlying the first phase of secretion. These elements, presumed to be Ca2+-calmodulin-dependent processes including CaM-dependent protein kinases, become more sensitive to activation by Ca2+ either because cAMP acts to enhance the sensitivity of CaM-dependent kinases to Ca2+, or because cAMP inhibits, by an unknown mechanism, the activity of phosphoprotein phosphatases. 

Fehse F, Trautmann M, Holst JJ. et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2005 90 5991-5997. 

This is a combination of a proportional control (first term of the parentheses) and a differential (second term). The beta cell is thus able to respond with a fast, but transient, response dependent on the rate of glucose change. This is demonstrated in Fig. 6.5b, where the glucose concentration increases from 5 mM to 10 mM as a logistic function with different slopes. The figure shows that there is an increasing overshoot for increasing slope. This type of differential control explains part of the so-called first phase of insulin release [33-35]. 

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