The overriding shared responsibility of insulin and glucagon is to maintain blood glucose within normal limits. Shown in Figure 1 are the dose-response curves of (i) how falling glucose levels stimulate glucagon release and (ii) how rising blood glucose levels stimulate the secretion of insulin. When the blood glucose concentration rises above ~5 mM then the β-cell begins to secrete insulin. The steep portions of the insulin release curve occur at blood concentrations of 10–11 mM glucose that occur postprandially. Conversely, the half-maximal glucose-mediated suppression of glucagon secretion occurs at a glucose concentration of 3–4 mM. These two dose-response curves describe the responses of the pancreatic α- and β-cells as they work to effect a stable blood glucose concentration.
Fig1. Effect of changes in blood glucose concentration on the inhibition of secretion of glucagon (blue) and stimulation of the secretion of insulin (red). These studies were carried out in in vitro perfused rat pancreas. R.G. Gosmanov, A.R.Gosmanov, and J.E. Gerich, Endotext website: Diabetes Mellitus and Carbohydrate Metabolism—DiabetesManager, 2. Glucagon Physiology (2012); available at www.endotext.org.
The principal biological actions of insulin and glucose are complex and interdependent upon the deli cate balance of anabolism and catabolism that occurs throughout the body in response to changes in caloric intake, caloric composition, and the degree of physical activity. In most situations the roles of insulin and glucagon are antagonistic. Tables 1 and 2, respectively, summarize the actions of insulin and glucagon in their principal target tissues, the liver, muscle, and adipose tissues.
Table1. Summary of Actions of Insulin on Several Tissues
Table2. Summary of Actions of Glucagon on Several Tissues in the Glucagon-Sufficient State
1. Liver
The “normal” blood glucose level is in the range of 80–110 mg/dL, whereas the chronic elevated blood glucose level associated with diabetes type 2 is >130 mg/dL. The chronic lowered blood glucose falls in the range of 50–60 mg/dL. The American Diabetes Association recommends a post meal glucose level of less than 180 mg/dL and a fasting plasma glucose of 90–130 mg/dL.
The actual amount of glucose in the blood and body fluid compartments is normally very small. In a healthy adult of 75 kg with a blood volume of 5 liters, a blood glucose level of 100 mg/dL amounts to a total of only~5 g of glucose. This is slightly less than two packets of sugar for a cup of coffee, but it should satisfy the consumer’s sugar receptors.
As shown in Figure 2, an average meal will provide 90 g of glucose or 270 g of glucose per three meals/ day. Thus a daily dietary influx will total ~270 g of sugar that will result in the ongoing elevation of blood glucose levels arising from the ingested three meals. Therefore per one meal, the homeostasis mechanisms summarized in Figure 2 must process 90 g of glucose to lower the blood glucose level back to the nor mal range of 80–110 mg/100 mL of glucose.
Fig2. Distribution of glucose after a meal between storage of glucose as glycogen or metabolism of glucose to CO2 and production of ATP. An average meal contains ~90 grams of glucose. In this example, muscle takes up 50% (~48 grams) of the ingested glucose of which half (24 grams) is stored in muscle as glycogen and half (24 grams) is metabolized by the glycolytic pathway and the TCA cycle to generate significant amounts of ATP which is utilized as an immediate source of energy. Approximately 17% (~15 grams) of the ingested glucose is transported directly to the brain where it is also metabolized to generate ATP to support brain activities. The brain does not store glycogen, and thus is dependent 24 hours/day upon a continuous uptake of blood glucose to support all the cells of the brain. The liver takes up ~20% (17 grams) of the meal’s 90 grams of glucose and stores it as glycogen. This hepatic glycogen is available to be released into the blood so as to maintain the blood glucose concentrations in the normal range, e.g., 80–110 g/100 mL. The kidneys take up ~10% (8 grams) of the glucose meal in the form of lactate which is released from red blood cells (RBC). Since RBC do not have mitochondria, they must release their anaerobically oxidized glucose as either lactate and/or pyruvate. Finally, in this model, adipose tissue has a modest ~2% (2 grams) uptake of glucose which is then converted to triglycerides for long-term storage. Source of this figure is from Marieb, E.N. & Hoehn, K. in Human Anatomy and Physiology, 7th Edition, Pearson Benjamin Cummings, San Francisco, (2005).
As shown in Figure 2, there are two physiological mechanisms that result in lowering of the blood glucose levels associated with a single meal: (a) one involves storage of ~50% of the excess glucose as glycogen; and (b) the second involves the metabolism of ~50% of the glucose by the process of glycolysis linked to the TCA cycle so as to generate substantial amounts of ATP. The elevated blood glucose levels stimulate insulin secretion from the pancreas (see Figure 2). This leads to an increased uptake of glucose and storage over 24 hours as glycogen by the liver (3 × 17 g), muscle (3 × 24 g), and fat/adipose (3 × 2 g). Over the same 24-hour time interval, the brain (3 × 15 g) and muscle (3 × 24 g) metabolize the indicated amounts of glucose via glycolysis linked to the TCA cycle to generate ATP for a wide array of ongoing energy-requiring activities. The kidneys also use 3 × ~8 g/meal lactate as an energy source.
The liver performs an indispensable role in maintaining an adequate blood level of glucose. It possesses the enzymatic capability either to generate glucose from stored glycogen or to store excess glucose as glycogen (Figure 3). The upper half of the figure focuses on the scenario of a “rising” blood glucose level while the lower half of the figure focuses on the circumstances of a falling blood glucose level. In addition, the liver contains an active gluconeogenesis capability that will permit the production of glucose from three- and four-carbon fragments derived from amino acids. Also, the liver can oxidatively metabolize glucose and other smaller metabolites to H2O and CO2, which generates ATP, or convert two-carbon fragments to larger free fatty acids, which then are incorporated into triglycerides and phospholipids.
Fig3. Regulation of blood glucose levels by insulin and glucagon. Comparison of the relative contributions of insulin and glucagon to the maintenance of normal blood glucose levels in a human. The figure shows the consequences of blood glucose levels deviating from the normal level of about 90 mg/100 mL of blood. The upper half of the figure focuses on the scenario of a “rising” blood glucose level, whereas the lower half of the figure focuses on a scenario of a “declining” blood glucose level. Modest elevation of glucose levels stimulates the pancreas to secrete insulin which in liver and muscle will stimulate storage of the excess glucose and the metabolic energy that it represents. In contrast, a modest fall in blood glucose levels (bottom half of the figure) stimulates the pancreas to secrete glycogen which stimulates glycogen breakdown to glucose only by the liver. Muscle does not have a glucagon receptor. Modified from Marieb, E.N. & Hoehn, K. (2005) Human Anatomy & Physiology, 7th Edition, Pearson, Benjamin Cummings, San Francisco, USA.
Several key enzymes in the liver are markedly affected by the presence or absence of glucagon or insulin. Activation of the glycogenolytic system involves the phosphorylation of key enzymes, while inactivation necessitates dephosphorylation. On the one hand glycogen is phosphorylyzed (broken down) by the cascade of cAMP-governed reactions that con vert the relatively inactive phosphorylase b into the more active phosphorylase a. On the other hand, under conditions where it is appropriate to convert glucose into glycogen, there is activation of a phosphatase that converts the phosphorylated D or dependent form of glycogen synthetase into the dephosphorylated I or independent form. A key feature of this system is the unique role played by the protein phosphorylase b kinase-kinase, which has two distinct catalytic activities. When it is phosphorylated (as a consequence of the presence of glucagon), it initiates the cascade that ultimately leads to the conversion of phosphorylase b into phosphorylase a and the production of glucose-1-P. Alternatively, when the phosphorylase b kinase-kinase is not phosphorylated, it acquires the activity of glycogen-I-synthetase-kinase. Thus, the presence of glucagon favors the generation of an active phosphorylase b kinase-kinase that leads to glucose formation, while the presence of insulin activates a phosphatase that leads to glycogen formation.
In addition to the glucagon–insulin modulation of glycogen storage and mobilization in the liver, these two peptide hormones also modulate the balance between gluconeogenesis and lipogenesis. Under circumstances of glucose demand, gluconeogenesis will predominate to convert glucose into those carbon skeletons derived from amino acids or glycolytic intermediates produced prior to pyruvate. Under conditions of glucose excess, glycolytic intermediates and free fatty acids can be directed either to (i) storage as triglycerides, (ii) to oxidation by the TCA cycle producing ATP, or (iii) to production of ketone bodies. Reversal of the glycolytic pathway requires access to NADH, whereas lipogenesis is dependent upon access to NADPH for fatty acid biosynthesis.
In summary, glucagon has been shown to stimulate the conversion of pyruvate, lactate, alanine, and glycerol into glucose. This is accomplished largely by modulating key enzymes of the gluconeogenic pathway. There appear to be no effects of glucagon on stimulating substrate supply or in increasing amino acid uptake by the liver. Insulin appears to exert its inhibitory effects on liver gluconeogenesis by (i) inhibiting or slowing the enzymes of gluconeogenesis and (ii) diminishing the flow of amino acids from peripheral tissues, principally muscle, to the liver.
Phosphorylated glycolytic intermediates are not capable of traversing the outer cell membrane of the liver. However, the liver contains an active glucose-6 phosphatase. The activity of this enzyme is increased in the absence of insulin or the presence of cortisol; this ensures the ready conversion of glucose 6-phosphate to free glucose, which may then be exported from the liver cell. By contrast, muscle cells do not have measurable glucose-6-phosphatase activity, and thus the muscle glycogen stores cannot be mobilized for the maintenance of blood glucose levels.
2. Muscle
In the absence of insulin there is a stimulation of net protein catabolism in muscle. The resulting free amino acids are released into the bloodstream and delivered to the liver where they are oxidatively deaminated. The resulting carbon fragments are then committed to gluconeogenesis or catabolism to yield ketone bodies and/ or CO2. The resulting increase in nitrogen is converted to urea and excreted in the urine.
Muscle tissue is known to contain insulin but not glucagon receptors. Insulin occupancy of these receptors leads to an increased uptake of both glucose and amino acids; there is also an associated stimulation of protein synthesis. After an overnight fast and in the absence of physical activity, muscle tissue is largely dependent upon the oxidation of free fatty acids to meet its energy demands. Under these conditions there would need to be a significant pool of muscle glycogen. With the initiation of mild-to-moderate exercise, the muscle tissue successively oxidizes its own glycogen, then blood glucose, and finally blood-delivered free fatty acids derived from adipose and hepatic stores.
3. Adipose Tissue
Adipose tissue is one of the principal target organs for insulin action. The extensive amount of triglycerides stored in adipocytes serves as an important fuel source under conditions of dietary caloric restriction or prolonged exercise. The mobilized free fatty acids are systematically delivered to a number of key organs (heart and kidney), which can directly utilize them as a substrate for oxidative metabolism. If the free fatty acids were taken up by the liver, they could be esterified into triglycerides or phospholipids, oxidized to CO2, or more likely converted into ketones, particularly β-hydroxybutyrate and acetoacetate. These ketones in turn can also serve as fuels for most extrahepatic tissues, particularly the brain, under conditions of very low blood glucose levels.
4. Pharmacological Agents Related to the Pancreas
Panels A and B of Figure 4 show the chemical structures of two classes of drugs currently used for treatment of diabetes types 1 and 2. Glipizide and glimepiride (panel A) are second-generation sulfonylureas that are useful in treatment of type 1 diabetes. They act by stimulating the secretion of insulin from the beta cells in the pancreas. Also there is some evidence that they can limit the production of glucose in the liver.
Fig4. Chemical structures of some of the most frequently employed oral antidiabetic compounds. (Panel A) The structure of two second-generation drugs, glipizide and glimepiride, that belong to the sulfonylurea class of compounds that have proven to be effective in treating type 2 diabetes. The inset “box” contains the structure of the sulfonylurea radical which is the “active” portion for both glipizide and glimepiride. (Panel B) The structure of one biguanide drug, metformin. The inset box shows the signature structure of the biguanide. Metformin is currently the only biguanide type drug currently available in the United States. (Panel C) The structures of alloxan and streptozotocin are illustrated. These are both drugs that are employed to induce diabetes by selectively destroying pancreatic β-cells in an experimental animal. Streptozotocin is an antibiotic produced by Streptomyces achromogenes var. streptozoticus that has been shown to inhibit the biosynthesis of DNA, including the DNA of pancreas β-cells.
Metformin (panel B) is clinically useful as a drug for treating type 2 diabetes where it reduces hepatic insulin resistance and, thereby, gluconeogenesis which results in release of glucose. The basis of metformin’s biological actions lies in its ability to activate adenosine monophosphate-activated protein kinase (AMPK), an enzyme that plays an important role in insulin signaling, which leads to favorable effects on body energy balance.
Both alloxan and streptozotocin (panel C) can disrupt the pancreatic islets so that insulin secretion is not occurring. Streptozotocin and alloxan can enter the β cells of the pancreatic islets by passage through the GLUT2 receptors present in the islet cell’s plasma membrane. This leads to an accumulation in the cytosol of alloxan which generates reactive oxygen species (ROS) by a complex series of coupled reactions that ultimately are responsible for the death of the pancreas beta cells.
After the arrival of streptozotocin in the cytosol of pancreas beta cells, it is split into its glucose and methylnitrosourea moieties. Due to streptozotocin’s alkylating properties, the latter fragments DNA leading to a modification of many biological macromolecules, which collectively then leads to a destruction of the beta cells. This results in a state of insulin-dependent diabetes.
