The endocrine part of the pancreas is the islets of Langerhans. The islets contain four major cell types, each of which secrete a specific hormone, as shown in Table 28.1. These hormones regulate energy metabolism by coordinating the secretion and storage of endogenous glucose, free fatty acids, amino acids, and ketone bodies. This ensures that energy needs are met during basal and active states.
Gap junctions connect α cells and β cells to themselves and each other, permitting rapid communication. Beta cells inhibit the activity of neighboring α cells and thereby suppress the release of glucagon.
28.1 Insulin, Glucagon, and Energy Metabolism
Insulin
Synthesis
Insulin is synthesized in pancreatic islet β cells in the form of a prohormone. This is a single polypeptide chain of 86 amino acids. Active insulin is generated by the proteolysis of C peptide by a specific endopeptidase, leaving two polypeptide chains joined by disulfide bonds. The A chain has 21 residues, and the B chain has 30 residues. C peptide, which is more stable than insulin, is cosecreted. Measurement of C peptide gives a reliable estimate of endogenous insulin production (Fig. 28.1).
Mechanism of Secretion
Glucose binds to a GLUT-2 transporter located in the plasma membrane of β cells and enters the cell by facilitated diffusion. Once inside, it is rapidly metabolized, generating adenosine triphosphate (ATP) and the reduced form of nicotinamide adenine dinucleotide (NADH). This rise in ATP levels causes K+ channels to close, resulting in depolarization of the β cell. Depolarization opens voltage-gated Ca2+ channels, and the subsequent Ca2+ influx stimulates release of insulin from stores (rapid release). This influx of Ca2+ also activates calmodulin and Ca2+/calmodulin-dependent protein kinase (CamK). This activation increases insulin synthesis (and slows the release of insulin).
Table 28.2 lists other glucose transporters, the tissues that express them, and their actions.
Regulation of Secretion
Table 28.3 lists the factors that regulate insulin secretion. Serum [glucose] is the main determinant.
Receptors and Cell Mechanisms
The insulin receptor is a tyrosine kinase receptor with extracellular α subunits and β subunits that span the cell membrane. When insulin binds to this receptor, it leads to intracellular auto-phosphorylation and the activation of signaling molecules (Fig. 28.1).
Insulin downregulates its own receptors, so the number of receptors is decreased in obesity and increased in fasting.
Oral antidiabetic drugs
Oral antidiabetic drugs are useful in the treatment of type II diabetes. Sulfonylurea drugs (e.g., tolbutamide and glimerpiri-dine) directly close ATP-sensitive K+ channels on the surface of pancreatic β cells, causing membrane depolarization and increased insulin secretion. Biguanides (e.g., metformin) decrease hepatic gluconeogenesis, and the absorption of glucose from the gastrointestinal (GI) tract. Metformin and thiazolidinediones agents (e.g., pioglitazone, and rosiglitazone) also increase insulin sensitivity in skeletal muscle and adipose tissue. Because metformin does not increase the release of pancreatic insulin, the risk of hypoglycemia is lower than with other sulphonylurea agents. α-Glycosidase inhibitors (e.g., acarbose and miglitol) are competitive, reversible inhibitors of intestinal α-glycosidase, which causes delayed absorption of carbohydrates, thereby blunting postprandial hyperglycemia.
Fig. 28.1 
Tyrosine kinase receptors.
The insulin receptor is a glycoprotein consisting of two α chains, located on the outside of the cell, and two β chains that are membrane bound and reach into the cytosol. Insulin binds to the exterior α chains, which phosphorylates part of the internal β chains. This activates tyrosine kinase, which then phosphorylates tyrosine R groups of a peptide (insulin receptor substrate, IRS-1), which, in turn, triggers further phosphorylation and dephosphorylation reactions, leading to the physiological effects of insulin. (ECF, extracellular fluid)
Actions
Insulin causes a reduction in serum [glucose] (principally). It does this by stimulating the up-take of glucose in tissues by the insertion of GLUT transporters into cell membranes. Insulin also increases the utilization of glucose as an energy source and promotes the storage of energy (as glycogen, protein, and fat).
Liver
– Insulin increases glycogen synthesis (and decreased glycolysis).
– Insulin decreases gluconeogenesis by shunting substrate away from glucose formation toward the production of fructose 2,6-bisphosphate. It does this by activating phosphofructokinase.
– Insulin decreases ketone formation.
Muscle
– Insulin increases the uptake of amino acids into skeletal muscle cells.
– Insulin increases protein synthesis and decreases protein degradation.
– Insulin increases glycogen synthesis (and decreases glycolysis).
Fat
– Insulin increases uptake of free fatty acids into adipose tissue.
– Insulin increases fat deposition and decreases fat degradation.
Pancreas
– Insulin decreases the secretion of glucagon.
Miscellaneous
– Insulin increases Na+−K+ ATPase activity, which promotes K+ uptake into cells (in exchange for Na+); thus, serum [K+] levels are reduced.
– Insulin increases cholesterol biosynthesis.
– Insulin also increases wound healing, microvascular integrity, neural integrity, and growth factors.
Insulin and potassium balance
Potassium is an important ion in the body, with 98% being intracellular. The ratio of intracellular to extracellular potassium determines cell membrane potential. Immediate potassium balance is controlled by intracellular and extracellular potassium exchange driven by the Na+−K+ ATPase pump. This is controlled by insulin and β2 receptors. Long-term potassium balance is controlled by renal excretion. In hyperkalemic (high potassium) states, glucose and insulin are used to drive potassium into cells by increasing the activity of the Na+−K+ ATPase pump.
Ketone formation
Ketones provide an alternative source of energy during periods of low glucose and after glycogen stores have been consumed. They are formed by the β oxidation of acetyl coenzyme A (acetyl-CoA), which is derived from fatty acids, in liver mitochondrial cells. Beta oxidation also yields NADH and the reduced form of flavin adenine dinucleotide (FADH2), which then undergoes oxidative phosphorylation, producing ATP. Acetyl-CoA from fatty acid catabolism would normally enter the citric acid cycle, producing energy (via the oxidative phosphorylation of NADH and FADH2). However, in periods of low glucose, oxaloacetate (a citric acid cycle intermediate) is used for gluconeogenesis, diverting acetyl-CoA for ketone formation. There are three ketones: acetoacetic acid, β-hydroxybutyric acid, and acetone. Acetone is produced from the spontaneous decarboxylation of acetoacetic acid, so it is produced in the least quantity of all of the ketones. Furthermore, acetone cannot be converted back to acetyl-CoA and is excreted in urine and exhaled (giving the breath a characteristic “fruity” smell in ketotic states).
Pathophysiology
Insulin deficiency. Insulin deficiency, or diminished effectiveness of endogenous insulin, leads to diabetes mellitus. There are two types of diabetes mellitus: type I and type II. These two types of diabetes are summarized in Tables 28.4 and 28.5.
Glucose tolerance test
The glucose tolerance test is used to test for type II diabetes. It involves giving the patient a known oral dose of glucose, following an 8- to 12-hour fasting period, then measuring plasma glucose levels at intervals thereafter to determine how quickly plasma glucose levels fall and homeostasis is regained. Normal fasting plasma glucose levels are < 6.1 mmol/L. Glucose levels of 6.1 to 7.0 mmol/L are considered borderline and are indicative of impaired fasting glycemia. Measurements of plasma glucose taken after 2 hours should be < 7.8 mmol/L. Glucose levels of 7.8 to 11.0 mmol/L indicate impaired glucose tolerance; levels ≥ 11.1 mmol/L allow the diagnosis of diabetes.
Diagnosis of type I diabetes
The diagnosis of type I diabetes is made by conducting various blood tests:
1. Glycated hemoglobin (A1c) test. This test measures the percentage of blood sugar attached to hemoglobin and is an indication of average blood sugar levels over the past 2 to 3 months. An A1c > 6.5% is diagnostic of diabetes. This test has yet to be adopted by the World Health Organization as the gold standard test for diabetes.
2. Random blood sugar level. A random blood test is taken and blood sugar measured. A value > 200 mg/dL (11.1 mmol/L) is suggestive of diabetes, especially if the patient has associated symptoms.
3. Fasting blood sugar test. The patient fasts overnight, and a blood sample is taken in the morning. A value > 126 mg/dL (> 7 mmol/L) on two separate occasions allows for a diagnosis of diabetes.
4. Oral glucose tolerance test.
If type I diabetes is diagnosed, the patient will also be screened for autoantibodies, which are commonly associated with diabetes.
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is a life-threatening complication of diabetes (usually type I diabetes). In DKA, there is a severe shortage of insulin, so the body ceases to use carbohydrate as an energy source and starts using fatty acids, which produce ketones (acetoacetate and β hydroxybutyrate). Dehydration (due to osmotic effect of glucose) occurs followed by acidosis (from ketones) and coma. Signs may include hyperventilation (to compensate for acidosis) and the breath smelling of ketones (sweet smell). DKA usually occurs in known diabetics and can be triggered by illness or inadequate/inappropriate insulin therapy. Treatment involves giving insulin, potassium, bicarbonate, and replacement fluids.
Insulin excess. Insulin excess is summarized in Table 28.6.
Central nervous system and hypoglycemia
The brain and spinal cord require glucose for energy and are therefore sensitive to large decreases in plasma glucose levels. If there is a gradual decrease in blood glucose, the CNS adapts by using ketone bodies, but this adaptation requires several weeks. Hypoglycemia inhibits insulin synthesis and secretion, causing a decrease of GLUT-4 transporters. This causes decreased glucose uptake in muscle and adipose tissue, thereby sparing glucose for the brain to use. The GLUT-3 transporter in neural tissue is not affected by insulin; hence, the brain can still use glucose in the absence of insulin.
Glucagon
Synthesis
Glucagon is synthesized in pancreatic islet α cells in the form of a prohormone, which is a single polypeptide chain. Active glucagon is a 29 amino acid peptide that is generated by limited proteolysis by a specific endopeptidase.
Regulation of Secretion
Table 28.7 lists all of the factors that modulate glucagon secretion.
Actions
Glucagon increases serum [glucose] by promoting the utilization of energy stores.
Liver
– Glucagon increases glycogen breakdown to glucose.
– Glucagon increases gluconeogenesis by decreasing the activity of phosphofructokinase. This reduces the formation of fructose 2,6-bisphosphate, and substrate is shunted toward glucose production.
– Glucagon increases ketone formation.
Muscle
– Glucagon has no influence on muscle tissue.
Adipose tissue
– Glucagon increases lipolysis. The fatty acids produced are used for gluconeogenesis.
Pancreas
– Glucagon decreases insulin secretion.
Miscellaneous
– Glucagon decreases cholesterol synthesis.
Pathophysiology
Glucagon excess. Table 28.8 summarizes glucagon excess.
Table 28.9 summarizes the effects of insulin and glucagon on glucose homeostasis and energy metabolism.
28.2 Effects of Other Hormones on Energy Metabolism
Several hormones besides insulin and glucagon interact to regulate blood glucose concentration under different physiological conditions. The effects of cortisol and epinephrine are listed in Table 28.10. Growth hormone acts similarly to insulin in the short term. Somatostain inhibits the secretion of insulin, glucagon, and gastrin.
