First Phase of Insulin Secretion

It always takes some short time before the change in S can inhibit GK, so S may overshoot after a fast change. As the translocation process is assumed to be much 

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]. 

When the differential control is added to the effect of GK translocation, the beta cell acts as a PID controller [36], but with nonlinear characteristics and with saturable signals. This is shown in Fig. 6.5c. The mutual effect of the three parts depends on the actual parameters of the model. Notice that for fast changes (kj =0.005 min-1), the integrator tends to saturate [32]. 

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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. 

The effect is a nerve-mediated increased insulin secretion, particularly increased first phase activity [41-43], but the effect on glucose uptake is more pronounced. It appears that the neural response can increase the translocation of GLUT4 much like the effect of exercise and without concomitant changes in insulin concentration [44]. 

Whatever the causes, the final result in type 1 DM is an extensive and selective loss of pancreatic /3 cells and a state of absolute insulin deficiency. In type 2 DM, fi-cell mass is generally reduced by -50%. At diagnosis, virtually all persons with type 2 DM have a profound defect in first-phase insulin secretion in response to an intravenous glucose challenge, although some of these fi-cell abnormalities may be secondary to desensitization by chronic hyperglycemia. 

In particular, loss of first-phase insulin secretion seems to be the first and most important defect of the beta cell. In the UKPDS, the decline in insulin secretion was strongly associated with disease progression [6]. In Pima Indians, development of diabetes mellitus was associated with only a modest deterioration in insulin sensitivity, but a major decrease in acute insulin response to glucose [7]. In addition, loss of first-phase insulin secretion has been shown to be a predictor of impaired glucose tolerance in the San Antonio Heart Study [8]. 

Besides the reduced insulin-mediated glucose uptake in skeletal muscle (and in liver and fat tissue), the abnormal insulin secretion pattern characterised by a lack of first-phase insulin release may also play a pathophysiological role, since the postprandial insulin peaks disappear in T2D subjects (Fig. 3). A recent publication has shown that the reduction of the first-phase insulin response to meals is already present at normal fasting glucose values in T2D subjects [13]. This indicates a need for an earlier insulin treatment than what has been the routine for several years. Furthermore, these findings indicate that it is unphysiological to treat... 

Quddusi S, Vahl TP, Hanson K, Prigeon RL, D Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first-and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care 2003 26 791-798. 

Fehse FC, Trautmann M, Holst JJ, Halseth AE, Fineman MS, Kim D, et al. Effects of exenatide on first and second phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes (Abstract). Diabetes 2004 53(Suppl. 2) A 83. 

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