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are largely governed by other stimuli (see later discussion) that act as amplifiers or inhibitors of the effects of glucose. The effectiveness of these agents therefore decreases as glucose concentration decreases.

Other Circulating Metabolites

Amino acids are important stimuli for insulin secretion. The transient increase in plasma amino acids after a protein-rich meal is accompanied by increased secretion of insulin. Arginine, lysine, and leucine are the most potent amino acid stimulators of insulin secretion. Insulin secreted at this time may facilitate storage of dietary amino acids as protein and prevents their diversion to gluconeogenesis. Amino acids are effective signals for insulin release only when blood glucose concentrations are adequate. Failure to increase insulin secretion when glucose is in short supply prevents hypoglycemia that might otherwise occur after a protein meal that contains little carbohydrate. Fatty acids and ketone bodies may also increase insulin secretion, but only when they are present at rather high concentrations. Because fatty acid mobilization and ketogenesis are inhibited by insulin, their ability to stimulate insulin secretion provides a feedback mechanism to protect against excessive mobilization of fatty acids and ketosis.

Hormonal and Neural Control portal vein. An increase in the concentration ofglucose in portal blood is detected by glucose sensors in the wall of the portal vein and the information is relayed to the brain via vagal afferent nerves. In response, vagal efferent nerves stimulate the pancreas to secrete insulin and the liver to take up glucose.

Insulin secretion by the human pancreas is virtually shut off by epinephrine or norepinephrine delivered to beta cells by either the circulation or sympathetic neurons. This inhibitory effect is seen not only as a response to low blood glucose, but may occur even when the blood glucose level is high. It is mediated through a2-adrenergic receptors on the surface of beta cells. Physiologic circumstances that activate the sympathetic nervous system thus can shut down insulin secretion and thereby remove the major restraint on mobilization of metabolic fuels needed to cope with an emergency.

Secretory activity of beta cells is also enhanced by growth hormone and cortisol by mechanisms that are not yet understood. Although they do not directly evoke a secretory response, basal insulin secretion is increased when these hormones are present in excess, and beta cells become hyperresponsive to signals for insulin secretion. Conversely, insulin secretion is reduced when either is deficient. Excessive growth hormone or cortisol decreases tissue sensitivity to insulin and can produce diabetes (see Chapter 42). The factors that regulate insulin secretion are shown in Fig. 20.

In response to carbohydrate in the lumen, the intestinal mucosa secretes one or more factors, called incretins, that reach the pancreas through the general circulation and stimulate the beta cells to release insulin even though the increase in blood glucose is still quite small. Incretins are thought to act by amplifying the stimulatory effects of glucose. This anticipatory secretion of insulin prepares tissues to cope with the coming influx of glucose and dampens what might otherwise be a large increase in blood sugar. Various gastrointestinal hormones including gastrin, secretin, cholecystokinin, glucagon-like peptide (GLP-1), and glucose-dependent insulinotropic peptide (GIP), can evoke insulin secretion when tested experimentally, but of these hormones, only GLP-1 and GIP appear to be physiologically important incretins.

Secretion of insulin in response to food intake is also mediated by a neural pathway. The taste or smell of food or the expectation of eating may increase insulin secretion during this so-called cephalic phase of feeding. Parasympathetic fibers in the vagus nerve stimulate beta cells by releasing acetylcholine or the neuropeptide VIP. Activation of this pathway is initiated by integrative centers in the brain and involves input from sensory endings in the mouth, stomach, small intestine, and

Cellular Events

Beta cells increase their rates of insulin secretion within 30 sec of exposure to increased concentrations of glucose and can shut down secretion as rapidly. The question of how the concentration of glucose is monitored and translated into a rate of insulin secretion has not been answered completely, but many of the glucose amino acids fatty acids ketones acetylcholine VIP GLP-1 GIP

glucagon glucose amino acids fatty acids ketones acetylcholine VIP GLP-1 GIP

glucagon

insulin

FIGURE 20 Metabolic, hormonal, and neural influences on insulin secretion.

insulin

FIGURE 20 Metabolic, hormonal, and neural influences on insulin secretion.

important steps are known. The beta cell has specific receptors for glucagon, acetylcholine, GLP-1, and other compounds that increase insulin secretion by promoting the formation of cyclic AMP or IP3 and DAG, but it does not appear to have specific receptors for glucose. To effect insulin secretion, glucose must be metabolized by the beta cell, indicating that some consequence of glucose oxidation, rather than glucose itself, is the critical determinant. Beta-cell membranes contain the glucose transporter GLUT 2, which has a high capacity, but relatively low affinity, for glucose. Consequently, as glucose concentrations increase above about 100 mg/dl, glucose enters the beta cell at a rate that is limited by its concentration and not by availability of transporters. It is likely that glucokinase, which is specific for glucose and catalyzes the rate-determining reaction for glucose metabolism in beta cells, has the requisite kinetic characteristics to behave as a glucose sensor. Mutations that affect the function of this enzyme result in decreased insulin secretion in response to glucose that may be severe enough to cause a form of diabetes.

Secretion of insulin, like secretion of other peptide hormones, requires increased cytosolic calcium. Perhaps through the agency of a calmodulin-activated protein kinase, calcium promotes movement of secretory granules to the periphery of the beta cell, fusion of the granular membrane with the plasma membrane, and the consequent extrusion of granular contents into the extracellular space. To increase insulin secretion, increased metabolism of glucose must somehow bring about an increase in intracellular calcium concentration. Linkage between glucose metabolism and intracellular calcium concentration appears to be achieved by their mutual relationship to cellular concentrations of ATP and ADP.

In resting pancreatic beta cells, efflux of potassium through open potassium channels maintains the membrane potential at about —70 mV. Some potassium channels in these cells are sensitive to ATP, which inhibits (closes) them, and to ADP, which activates (opens) them. When blood glucose concentrations are low, the effects of ADP predominate even though its concentration in beta cell cytoplasm is about 1000 times lower than that of ATP. Because glucose transport is not rate-limiting in beta cells, increased concentrations in blood accelerate glucose oxidation and promote ATP formation at the expense of ADP. As a result, ADP levels become insufficient to counter the inhibitory effects of ATP, and potassium channels close. The consequent buildup of positive charge within the beta cell causes the membrane to depolarize, which activates voltage-sensitive calcium channels. When the depolarizing membrane potential reaches about —50 mV, calcium channels open. An influx of positively charged calcium reverses the membrane potential. Electrical recording of these events produces a pattern of voltage changes that resembles an action potential. The frequency and duration of electrical discharges in beta cells increase as glucose concentrations increase. In addition to triggering insulin secretion, elevated intracellular calcium inhibits voltage-sensitive calcium channels, and activates calcium-sensitive potassium channels allowing potassium to exit and the cell to repolarize (Fig. 21).

Although entry of calcium triggers insulin secretion, it appears that glucose and the various hormonal modulators may stimulate secretion by acting at additional regulatory sites downstream from calcium. Hormones and neurotransmitters that increase insulin

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