Glucagon

Biosynthesis, Secretion, and Metabolism

Glucagon is a simple unbranched peptide chain that consists of 29 amino acids and has a molecular weight of about 3500. Its amino acid sequence has been remarkably preserved throughout evolution of the vertebrates. The glucagon gene, which is located on chromosome 2, is expressed primarily in the alpha cells, L cells of the intestinal epithelium, and discrete brain areas. It encodes a large, 158-amino-acid preproglucagon protein that is processed in a tissue-specific manner to give rise to at least six biologically active peptides that contain similar amino acid sequences. In alpha cells the prepro-glucagon molecule is enzymatically cleaved to release glucagon and the major proglucagon fragment (Fig. 2).

In the intestine and the hypothalamus, the principal cleavage products are the glucagon-likepeptide 1 (GLP-1), which has important effects on islet function (see later discussion), and glucagon-like peptide 2 (GLP-2), whose major actions are exerted on the intestine. GLP-1 may also regulate the rate of gastric emptying and feeding behavior. Proglucagon is a member of a superfamily of genes that encodes gastrointestinal hormones and neuro-peptides including secretin, vasoactive inhibitory peptide (VIP), pituitary adenylyl cyclase activating peptide (PACAP), glucose-dependent insulinotropic peptide (GIP), and the growth hormone-releasing hormone, GHRH. Glucagon is packaged, stored in membrane-bound granules, and secreted by exocytosis like other peptide hormones.

Glucagon circulates without binding to carrier proteins and has a half-life in blood of about 5 min. Its concentrations in peripheral blood are considerably lower than in portal venous blood. This difference reflects not only greater dilution in the general circulation but also the fact that about 25% of the secreted glucagon is destroyed during passage through the liver. The kidney is another important site of degradation, and a considerable fraction of circulating glucagon is destroyed by plasma peptidases.

Physiologic Actions of Glucagon

The physiologic role of glucagon is to stimulate hepatic production and secretion of glucose and, to a lesser extent, ketone bodies, which are derived from fatty acids. Under normal circumstances, liver and possibly pancreatic beta cells are the only targets of glucagon action. A number of other tissues including fat and heart express glucagon receptors, and can respond to glucagon experimentally, but considerably higher concentrations of glucagon are needed than are normally found in peripheral blood. Glucagon stimulates the liver to release glucose and produces a prompt increase in

FIGURE 2 Cell-specific post-translational processing of preproglucagon. GRPP, glicentin related pancreatic peptide; GLP-1, glucagon-like peptide-1; GLP-2, glucagon-like peptide-2; IP2, intervening peptide 2. Intervening peptide-1 is the small fragment between glucagon and the major glucagon fragment at the top of the figure.

FIGURE 2 Cell-specific post-translational processing of preproglucagon. GRPP, glicentin related pancreatic peptide; GLP-1, glucagon-like peptide-1; GLP-2, glucagon-like peptide-2; IP2, intervening peptide 2. Intervening peptide-1 is the small fragment between glucagon and the major glucagon fragment at the top of the figure.

blood glucose concentration. Glucose that is released from the liver is obtained from breakdown of stored glycogen (glycogenolysis) and new synthesis (gluconeo-genesis). Because the principal precursors for gluconeo-genesis are amino acids, especially alanine, glucagon also increases hepatic production of urea (ureogenesis) from the amino groups. Glucagon also increases production of ketone bodies (ketogenesis) by directing metabolism of long-chain fatty acids toward oxidation and away from esterification and export as lipoproteins. Concomitantly, glucagon may also promote breakdown of hepatic triglycerides to yield long-chain fatty acids, which, along with fatty acids that reach the liver from peripheral fat depots, provide the substrate for ketogenesis.

All of the effects of glucagon appear to be mediated by cyclic AMP (see Chapter 2). In fact, it was studies of the glycogenolytic action of glucagon that led to the discovery of cyclic AMP and its role as a second messenger. Activation of protein kinase A by cyclic AMP results in phosphorylation of enzymes, which increases or decreases their activity, or phosphorylation of the transcription factor CREB, which usually increases transcription of target genes. Glucagon may also increase intracellular concentrations of calcium by a mechanism that depends on activation of protein kinase A, and the increased calcium may reinforce some actions of glucagon, particularly on glycogenolysis.

Glucose Production

To understand how glucagon stimulates the hepato-cyte to release glucose, we must first consider some of the biochemical reactions that govern glucose metabolism in the liver. Biochemical pathways that link these reactions are illustrated in Fig. 3. It is important to recognize that not all enzymatic reactions are freely reversible under conditions that prevail in living cells. Phosphorylation and dephosphorylation of substrate usually require separate enzymes. This sets up substrate cycles, which would spin futilely in the absence of some regulatory influence exerted on either or both opposing reactions. These reactions are often strategically situated at or near branch points in metabolic pathways and can therefore direct flow of substrates toward one fate or another. Regulation is achieved both by modulating the activity of enzymes already present in cells and by increasing or decreasing rates of enzyme synthesis and therefore amounts of enzyme molecules. Enzyme activity can be regulated allosterically by changes in conformation produced by substrates or cofactors, or covalently by phosphorylation and dephosphorylation of regulatory sites in the enzymes themselves. Changing the activity of an enzyme requires only seconds, whereas glucose

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