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Voltage-gated Ca2+ channel figure 7-23 Model describing cellular events linking occupancy of a membrane glucose receptor to secretion of insulin by the pancreatic /3-cell. The membrane glucose receptor is proposed to be the high Km passive glucose transporter, GLUT-2 (see Table 7-9). The Km of the transporter for glucose is =»17 mM; thus, the influx of glucose into the ¡3-cell is proportional to the blood glucose level up to 10-12 mM. The glucose that enters the /3-cell is phosphorylated by glucokinase to yield glucose 6-phosphate. The increased concentration of glucose 6-phosphate stimulates glycolysis and oxidative metabolism, thereby increasing the ratio of [ATP]/[ADP]. The increased [ATP] / [ADP] ratio is proposed to inhibit the ATP-sensitive K+ channels; the resultant depolarization of the plasma membrane triggers the opening of the voltage-gated Ca2+ channels so that there is an influx of Ca2+. The resulting increase in cytosolic [Ca2+] acts to stimulate the fusion of the insulin-containing granules with the (3-cell membrane. [Modified with permission from Efrat, S., Tal, M., and Lodish, H. F. (1994). The pancreatic /3-cell glucose sensor. Trends Biochem. Sci. 19, 535-538.]

glucose suppression of glucagon release stimulated by amino acids and of glucose stimulation of insulin secretion. The chemistatic properties of the a- and /3-cells toward the prevailing blood glucose concentration are nicely interdependent. The /3-cell threshold for glucose is ~5 mM, while the a-cell threshold for an amino acid mixture is 10 mM, provided that glucose is already present. The steep portions of the insulin release curve occur at blood concentrations of amino acids and glucose that occur postprandially. Conversely, the halfmaximal glucose-mediated suppression of glucagon secretion occurs at a glucose concentration of 3 mM. These two dose-response curves describe the responses of the a- and /3-cells as they work to effect a stable blood glucose concentration.

Given the possibility of metabolic interconversion of amino acids, fatty acids, and glycogen into glucose in liver, muscle, or adipose tissue, and given the reality of a changing dietary intake of these same nutrients, it is to be anticipated that these fuel metabolites themselves would coordinately modulate glucagon and insulin secretion. These relationships are incorporated into the model of a fuel receptor in a pancreatic /3-cell receptor illustrated in Figure 7-24 and are further illustrated schematically in Figure 7-26.

Figure 7-26 schematically describes the secretion of insulin and glucagon under the conditions of (i) a normal basal metabolic state, (ii) exercise, and (iii) after ingestion of a carbohydrate meal. A crucial function of the integrated operation of the a-/3-cell unit is to permit the appropriate regulation of the homeostasis of nutrients, such as amino acids, by allowing increases in the secretion of insulin without the danger of concomitant hypoglycemia. Thus, the aminogenic actions of insulin, which are manifest after the ingestion of a "protein-rich" meal, do not lead to hypoglycemia because there is a coupled stimulation of glucagon release; the glucagon then initiates hepatic glycogenol-ysis and increased release by the liver of as much glucose as leaves the extracellular space as a consequence of the insulin-mediated cellular uptake of glucose. Similarly, this same coupling of a- and /3-cells makes possi-

figure 7-24 Model of a hypothetical fuel receptor in a pancreatic /3-cell. The cell membrane of the islet cell is postulated to contain five coupled systems: (1) the substrate carriers, which may or may not function as fuel receptors; (2) a receptor-transducer complex with fuel receptors (e.g., for hexoses, glyceraldehyde, and a-ketoisocaproate) on the outside and sites for various fuel-derived metabolites and cofactors (e.g., A, B, C) on the inside of the membrane; (3) a Ca2+ gate that controls Ca2+ entry; (4) the adenylate cyclase system; and (5) the secretory complex comprising microtubule and secretory granules involved in the process of exocytosis driven by, Ca2+ and cAMP. [Modified from Matschinsky, F. M., Pagliara, A. A., Zawalich, W. S., and Trus M. D. (1979). Metabolism of pancreatic islets and regulation of insulin and glucagon secretion. In "Endocrinology" (L. J. DeGroot et al., eds.), Vol. 2, p. 946. Grune & Stratton, New York.]

figure 7-24 Model of a hypothetical fuel receptor in a pancreatic /3-cell. The cell membrane of the islet cell is postulated to contain five coupled systems: (1) the substrate carriers, which may or may not function as fuel receptors; (2) a receptor-transducer complex with fuel receptors (e.g., for hexoses, glyceraldehyde, and a-ketoisocaproate) on the outside and sites for various fuel-derived metabolites and cofactors (e.g., A, B, C) on the inside of the membrane; (3) a Ca2+ gate that controls Ca2+ entry; (4) the adenylate cyclase system; and (5) the secretory complex comprising microtubule and secretory granules involved in the process of exocytosis driven by, Ca2+ and cAMP. [Modified from Matschinsky, F. M., Pagliara, A. A., Zawalich, W. S., and Trus M. D. (1979). Metabolism of pancreatic islets and regulation of insulin and glucagon secretion. In "Endocrinology" (L. J. DeGroot et al., eds.), Vol. 2, p. 946. Grune & Stratton, New York.]

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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