Insulin - continued secretion

As noted In the chapter Introduction, all eukaryotic cells continuously secrete certain proteins, a process commonly called constitutive secretion. Specialized secretory cells also store other proteins In vesicles and secrete them only when triggered by a specific stimulus. One example of such regulated secretion occurs In pancreatic p cells, which store newly made Insulin In special secretory vesicles and secrete Insulin In response to an elevation In blood glucose (see Figure 15-7). These and other secretory cells simultaneously utilize two different types of vesicles to move proteins from the trans-Golgi network to the cell surface regulated transport vesicles, often simply called secretory vesicles, and unregulated transport vesicles, also called constitutive secretory vesicles. 

In healthy individuals, insulin is typically secreted continuously into the bloodstream at low basal levels, with rapid increases evident in response to elevated blood sugar levels. Insulin secretion usually peaks approximately 1 h after a meal, falling off to base levels once again within the following 2 h. 

Glycolytic oscillations in yeast cells provided one of the first examples of oscillatory behavior in a biochemical system. They continue to serve as a prototype for cellular rhythms. This oscillatory phenomenon, discovered some 40 years ago [36, 37] and still vigorously investigated today [38], was important in several respects First, it illustrated the occurrence of periodic behavior in a key metabolic pathway. Second, because they were soon observed in cell extracts, glycolytic oscillations provided an instance of a biochemical clock amenable to in vitro studies. Initially observed in yeast cells and extracts, glycolytic oscillations were later observed in muscle cells and evidence exists for their occurrence in pancreatic p-cells in which they could underlie the pulsatile secretion of insulin [39]. 

In the ebb phase, there is increased activity of the sympathetic nervous system and increased plasma levels of adrenaline and glucocorticoids but a decreased level of insulin. This results in mobilisation of glycogen in the liver and triacylglycerol in adipose tissue, so that the levels of two major fuels in the blood, glucose and long-chain fatty acids, are increased. This is, effectively, the stress response to trauma. These changes continue and are extended into the flow phase as the immune cells are activated and secrete the proinflammatory cytokines that further stimulate the mobilisation of fuel stores (Table 18.2). Thus the sequence is trauma increased endocrine hormone levels increased immune response increased levels of cytokines metabolic responses. 

In 1985 Nerup and co-workers demonstrated that treatment of isolated rat and human islets with conditioned media derived from activated mononuclear cells resulted in the inhibition of glucose-stimulated insulin secretion (Mandrup-Poulsen et cd., 1985). The cytokine IL-1/3 was found to be the active component of the conditioned media (Bendtzen etal., 1986). Mandrup-Poulsen et al. (1986) further showed that continuous exposure of islets to IL-1 is toxic. 

Treatment of sulfonylurea-induced hypoglycemia and of overdose with sulfonylureas has been reviewed (69). If intravenous dextrose is insufficient, octreotide is recommended (70) but not diazoxide. In patients with insulin reserve, dextrose can stimulate insulin secretion and paradoxically worsen the condition. Patients with drug-induced hypoglycemia should not be given glucagon, since it will stimulate insulin secretion. Hypoglycemia can last for up to 5 days. Continued observation is important, because recurrence after temporary recovery is common. 

Fig. 2.1 Examples of ultradian oscillations in human insulin secretion and blood glucose concentration (a) during continuous enteral nutrition and (b) during constant glucose infusion. Closer inspection shows that the glucose oscillations lead the insulin oscillations by a few minutes. Redrawn from [39, 40].

AlC levels fell continuously from 8.02 1.04 to 7.37 1.09. Improvement was noted from nine to twelve weeks with 200 or 300 mg of Pycnogenol. There was no difference in insulin levels, indicating that beneficial changes did not owe to increased insulin secretion. 

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