Normal Structure and Function


Hormones produced by the islets of Langerhans are the key regulators of the intermediary metabolism of carbohydrates, lipids, and proteins.

Insulin is a polypeptide formed from inactive precursors.

Insulin is a short polypeptide composed of 51 amino acids arranged into two chains linked together by two disulfide bonds (Fig. 10-3). Insulin synthesis occurs in several steps:


Anatomy and Physiology

Glucagon Polypeptide hormone produced by insular alpha cells that regulates the metabolism of carbohydrates. It promotes glycogenolysis in the liver, thus causing hyperglycemia. It may be produced by some pancreatic endocrine tumors (glucagonomas).

Glucose Key component of carbohydrate metabolism, present in free form in the blood or complexed into oligo- and polysaccharides in tissues. The normal concentration of glucose in serum or plasma is 70 to 110 mg/dL (3.9–6.1 mmol/L).

Insulin Polypeptide hormone produced by insular beta cells that is involved in regulating the metabolism of carbohydrates, lipids, and proteins. It has many functions, the most important of which is the promotion of glycogenesis in the liver and the uptake and utilization of glucose in muscle, fat cells, and several other tissues, thus lowering the blood concentration of glucose. It may be produced by some pancreatic endocrine tumors (insulinomas).

Insulin receptor Tyrosine kinase-linked cell membrane receptor that binds circulating insulin. Its activation leads to metabolic changes, the most important of which is increased influx and utilization of glucose. Defective function of insulin receptors leads to diabetes mellitus type 2.

Islets of Langerhans Endocrine part of the pancreas. Each islet is composed of several cell types: alpha cells that secrete glucagon, beta cells that secrete insulin, delta cells that secrete somatostatin, and F cells that secrete pancreatic polypeptide.

Pancreatic polypeptide Polypeptide secreted by endocrine and exocrine pancreatic cells and intestinal cells. It inhibits the secretion of pancreatic enzymes and the contraction of the gallbladder.

Somatostatin Polypeptide hormone produced by insular delta cells and intestinal endocrine cells. It inhibits the release of several other hormones, such as growth hormone, glucagons, insulin, and gastrin. It may be produced by some pancreatic or intestinal endocrine tumors (somatostatinomas).

Vasoactive intestinal polypeptide Polypeptide hormone widely distributed in the body, but most prominently found in the central nervous system and intestines. It leads to intestinal vasodilatation and hypermotility, as well as gastrointestinal water and electrolyte secretion. It may be produced by some pancreatic endocrine tumors (VIPomas).

Diseases of Endocrine Pancreas

Diabetes mellitus Metabolic syndrome characterized by hyperglycemia related to absolute or relative insulin deficiency or tissue resistance to insulin.

Gastrinoma syndrome Metabolic syndrome also known as Zollinger-Ellison syndrome, caused by gastrin-secreting tumors, most often located in the head of the pancreas. It is characterized by hypergastrinemia, gastric acid hypersecretion, and peptic ulcers that are often multiple and found in atypical locations. It is also sometimes characterized by a resistance to conventional antiulcer therapy.

Glucagonoma syndrome Metabolic syndrome caused by glucagonoma (i.e., a glucagon-secreting islet cell tumor composed of alpha cells). The syndrome includes mild diabetes, migratory erythematous skin necrosis, anemia, thrombosis, and a predisposition to bacterial infections.

Hyperglycemia Increased concentration of glucose in serum (>120 mg/dL), typically seen in diabetes mellitus as well as in a variety of endocrine diseases (e.g., Cushing’s syndrome, hyperthyroidism) and acute pancreatitis. Any type of shock increases serum glucose levels. It may be also drug-induced (e.g., by thiazide diuretics, phenytoin, and epinephrine).

Hypoglycemia Decreased concentration of glucose in serum (<40 mg/dL). Reactive hypoglycemia may occur after feeding (postprandial hypoglycemia). Fasting hypoglycemia is typically found in association with insulinoma, insulin abuse, or insulin overdose (in diabetic patients), but may be also found in association with some glycogen-storing or -consuming tumors and in severe systemic diseases.

Insulinoma syndrome Syndrome caused by insulinoma (i.e., an insulin-secreting islet cell tumor composed of beta cells). It is characterized by hypoglycemia, sweating, nervousness, lethargy, or fainting that may occasionally progress to hypoglycemic coma.

Islet cell tumors Group of endocrine tumors originating from the islets of Langerhans. These tumors may be benign or malignant, solitary or multiple, hormonally active or inactive. On the basis of the type of cells that form these tumors they are classified as insulinomas (most common), glucagonomas, gastrinomas, somatostatinomas, vasoactive intestinal polypeptide-secreting tumors (VIPomas), or pancreatic polypeptide-secreting tumors (PPomas). Histologically they resemble carcinoid tumors of the gastrointestinal and respiratory tract. By electron microscopy they contain dense membrane-bounded granules. Highly malignant tumors may resemble small-cell (oat cell) carcinomas of the lung.

Somatostatinoma syndrome Metabolic syndrome caused by somatostatinomas (i.e., somatostatin-secreting islet cell tumors). It is characterized by mild diabetes, steatorrhea, gastric hypochlorhydria, and gallstones.

VIPoma Metabolic syndrome, also known as Verner-Morrison syndrome, caused by VIPomas (i.e., pancreatic islet tumors composed of vasoactive polypeptide [VIP]-secreting cells). It is characterized by watery diarrhea, hypokalemia, and gastric hypochorhydria or even achlorhydria.

Secretion of insulin and glucagon is regulated by blood glucose, other metabolites, and some hormones.

Insulin and glucagon have diametrically opposite effects on the intermediary metabolism, and thus it is logical that the regulation of the synthesis and release of these two hormones is closely interlinked.

Factors that regulate the secretion of insulin can be classified as stimulatory and inhibitory.

Glucagon secretion is regulated by the same factors that regulate insulin secretions, but in a reverse manner.

Insulin and glucagon regulate the intermediary metabolism of carbohydrates, lipids, and proteins.

The actions of insulin and glucagons are closely interlinked. Insulin has predominantly anabolic effects and is “anticatabolic,” whereas glucagon has predominantly catabolic effects (Fig. 10-4). This is reflected in the blood insulin-to-glucagon ratio, which is high in the fed condition and low in a fasting state.

Insulin acts predominantly on liver, muscle, and fat tissue.

Glucagon acts predominantly on the liver, and it counteracts the hypoglycemic effects of insulin. In the liver it stimulates glycogenolysis by promoting the breakdown of glycogen into glucose. It stimulates gluconeogenesis (i.e., the formation of glucose from lactate or amino acids). Both effects lead to an increased concentration of glucose in the blood. Glucagon promotes the oxidation of fatty acids, which results in the formation of ketone bodies from acetyl CoA. It also stimulates the uptake of amino acids in the liver.

The main effects of insulin and glucagon are listed in Table 10-1.

Clinical and Laboratory Evaluation of Diseases of the Endocrine Pancreas


Except for diabetes mellitus (DM), which affects millions of people worldwide, other diseases of the endocrine pancreas are relative rare. Hence, in this chapter the major emphasis is on DM and its complications. The risk factors for DM and other less common pancreatic endocrine disorders can be discovered by careful taking of the patient’s history and are listed in Table 10-2.

Table 10-2 Risk Factors for Diabetes Mellitus (DM) and Other Less Common Pancreatic Endocrine Disorders

Hereditary factors
Social/nutritional factors Obesity-related type 2 DM
Other diseases of the pancreas Acute and chronic pancreatitis and secondary DM
Other endocrine diseases Hyperglycemia due to Cushing’s syndrome, or acromegaly
Medical and surgical procedures DM after resection of the pancreas for tumors
Drugs Drug-induced hyperglycemia or DM
External mechanical factors Pancreatic necrosis due to seat belt trauma and secondary DM

The American Diabetes Association (ADA) recommends screening for type 2 diabetes in all adults older than 45 years who have one or more risk factors. Screening should be repeated every 3 years thereafter. Fasting glucose testing of plasma is the preferred test, but one may use random plasma or serum glucose measurements also. If a random plasma glucose is 160 mg/dL or more, a fasting plasma glucose should be measured.

Increased incidence of type 2 diabetes in children and adolescents has prompted the ADA to recommend screening of children at age 10 years if the child has the following risk factors:


The most important clinical findings pointing to DM or other endocrine pancreatic disorders are:

Polyuria and polydipsia are common manifesting signs of diabetes mellitus.

Polyuria is defined as an excessive volume of urine, typically over 3 L/day. In DM it is typically combined with excessive excretion of glucose and thus it is best classified as osmotic. Loss of water elicits dehydration, which in turn causes thirst. Typically polyuria is thus accompanied by polydipsia (increased intake of water).

It is important to note that polyuria may be related to excessive intake of water, as in people who have an urge to drink (“psychogenic polydipsia”), and other endocrine disorders (e.g., hyperparathyroidism and other forms of hypercalcemia). Many intracranial lesions interfering with the secretion of the antidiuretic hormone (ADH) may cause “cranial” diabetes insipidus. Several renal diseases and drugs and toxins that affect the kidneys may manifest as “nephrogenic diabetes insipidus” (Table 10-3).

Table 10-3 Causes of Polyuria

Psychogenic polydipsia Water intake ↑ Plasma sodium → or ↓
Diabetes mellitus Osmotic water loss Plasma osmolality ↓
Hyperparathyroidism Osmotic water loss Plasma/urine glucose ↑
Cranial diabetes insipidus (reduced renal water reabsorption) Lack of ADH Plasma/urine calcium ↑
Renal diseases Inability to concentrate urine Urine osmolality ↓ (<600 mOsm/kg)
Drugs (e.g., lithium) Renal effects Plasma osmolality ↑ (>300 mOsm/kg)
Heavy-metal toxicity Renal effects Other signs of kidney disease

ADH, antidiuretic hormone; →, normal; ↓, reduced; ↑, increased.

Polyuria is a complication of hyperglycemia, which leads to glucosuria. Glucose in the urine “draws out” the water and thus leads to an osmotic polyuria. It is associated with a loss of fluid, minerals, and glucose in the urine. Dehydration may cause clinical symptoms such as dry skin and mucosal surfaces and reduced skin turgor. A hyperglycemia-related hyperosmolar state may cause blurry vision because of exposure of the lens and retina to hyperosmolar plasma. Reduced plasma volume (hypovolemia) may cause hypotension, syncope, and dizziness.

Polyphagia results from increased metabolic demands.

Many patients who develop type 1 DM have increased appetite and consume large amounts of food (polyphagia). Even though these patients eat a lot they tend to lose weight. Subcutaneous fat may appear depleted.

The reasons for polyphagia are not quite obvious but are directly or indirectly related to disturbances of the feeling of hunger. The eating behavior of each person is a function of hypothalamic centers known as the satiety and hunger centers (Fig. 10-5). These centers receive numerous impulses, which can be classified as anorexigenic (i.e., suppressing appetite) or orexigenic (promoting appetite). The secretion of orexins that act on the hunger center is stimulated by low glucose concentration in the blood. This correlates with the well-known fact that hypoglycemia, induced by exogenous insulin or insulin-producing tumors, manifests with hunger. Patients who have type 1 DM apparently lose the function of “glucose-sensitive neurons” and persistently secrete orexins. Another stimulus for overeating in type 1 DM might be a lack of glucagon or cholecystokinin (CCK), a pancreaticointestinal polypeptide that under normal circumstances inhibits hunger. The effects of CCK are seen only in the presence of an intact vagus nerve, which may be affected by diabetic neuropathy or the hyperosmotic state caused by hyperglycemia. Catecholamines, and especially norepinephrine, which are elevated in type 1 DM due to stress and poor glycemic control, also act by stimulating eating.

Longer lasting effects on the hunger center are most likely coming from the fat cells. Under normal circumstances fat cells secrete an appetite-suppressing substance called leptin. A lack of insulin leads to a loss of peripheral fat, causing a reduced secretion of leptin. Polyphagia and obesity typically found in type 2 DM are multifactorial and usually precede the development of clinical symptoms of DM.

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