Chapter 10 THE ENDOCRINE PANCREAS

Introduction

The endocrine pancreas consists of the islets of Langerhans, which are scattered between the acini and ducts of the exocrine part of the gland. The clinical syndromes related to the pathology of the islets of Langerhans result from either underproduction or overproduction of hormones normally produced by the cells forming the islets. The most important disease resulting from the underproduction of insular hormones is diabetes mellitus (DM). The syndromes related to overproduction of insular hormones are typically caused by tumors, which are also discussed here (Fig. 10-1). These tumors are relatively rare, accounting for 1% to 3% of all pancreatic neoplasms.

Figure 10-1 Clinically important diseases of the endocrine pancreas include diabetes mellitus and endocrine pancreatic tumors.

Normal Structure and Function

PHYSIOLOGY

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

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.

Stimulation of insulin release. High blood glucose directly stimulates beta cells, and it is thus the most important stimulus for insulin production and release. Other food constituents and metabolites, such as amino acids and fatty acids, may stimulate insulin release directly, but most often their effect is indirect, since these metabolites affect the utilization or release of glucose into the bloodstream. Intestinal secretin, released on feeding, stimulates insulin release. Cortisol and growth hormone induce peripheral insulin resistance and increase blood glucose concentration, thus stimulating the release of insulin.

Inhibition of insulin release. Insulin secretion is reduced physiologically during starvation and decreased food intake. Acute inhibition of insulin secretion during stress or trauma is mediated by epinephrine, which stimulates release of glucose from the liver and fatty acids from fat tissues, but also acts on pancreatic beta cells to decrease their sensitivity to glucose. Somatostatin has a paracrine inhibitory effect on insulin secretion.

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

Stimulation of glucagon release. The most potent stimulus for glucagon release is low blood glucose concentration, as occurs in hunger. Epinephrine release during stress or trauma also promotes glucagon release. It also overrides the effects of excess glucose release from the liver, which acts directly on the insular cells. Amino acids also stimulate glucagon release, thus counteracting their stimulatory effect on insulin release.

Inhibition of glucagon release. The most important inhibitor is high blood glucose concentration. Ketone bodies and free fatty acids have the same effect.

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.

Figure 10-4 Effects of insulin and glucagons on intermediary metabolism in the liver, muscles, and peripheral fat tissue. FFA, free fatty acid; TG, triglyceride.

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

Liver. In the liver it promotes storage of glucose in the form of glycogen by promoting glycogen formation and its lysis into glucose. The net outflow of glucose from the liver is reduced. Excess glucose is used for the synthesis of lipids, which are stored in liver cells in the form of triglycerides (TGs). Insulin also affects lipid metabolism by inhibiting ketogenesis and promoting synthesis of very low density lipoproteins (VLDLs). When VLDLs are released into the bloodstream they are taken up by muscle cells or fat cells and stored or used for energy production. Insulin stimulates the uptake of amino acids into liver cells.

Muscle. In the muscles insulin promotes the uptake of glucose from the blood and glycogen synthesis. It also inhibits glycogen phosphorylase and slows down glycogenolysis. Insulin stimulates the entry of amino acids into muscle cells and protein synthesis.

Fat tissue. Insulin stimulates glucose uptake and promotes TG storage by promoting the uptake of fat and fatty acid esterification and by inhibiting lipolysis of TGs.

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.

Table 10-1 Metabolic Effects of Insulin and Glucagon

Somatostatin inhibits the secretion of insulin and glucagon.

Somatostatin is produced by the delta cells. It acts locally in a paracrine manner on alpha and beta cells; in an autocrine manner by inhibiting its own release from δ cells; and in an endocrine manner on absorptive, secretory, and contractile cells of the gastrointestinal system. Somatostatin release is stimulated by high levels of blood glucose, some amino acids, and also in a local paracrine manner by glucagon. Its paracrine effects are inhibitory, and it suppresses the release of both insulin and glucagon. It also inhibits pancreatic exocrine secretion.

Clinical and Laboratory Evaluation of Diseases of the Endocrine Pancreas

FAMILY AND PERSONAL HISTORY

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

TYPE OF RISK FACTOR	SPECIFIC DISEASES–RISK FACTOR ASSOCIATIONS
Hereditary factors	Type 1 and type 2 DM Multiple endocrine neoplasia syndromes
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:

Overweight (BMI >85th percentile or weight 120% of ideal)

Family history of diabetes

High risk race/ethnicity (e.g., Native Americans, Hispanic Americans)

Signs of insulin resistance (e.g., dyslipidemia, acanthosis nigricans, hypertension, or polycystic ovary syndrome)

PHYSICAL EXAMINATION AND HISTORY OF PRESENT DISEASE

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

Increased incidence of bacterial infections

Sensory disturbances

Coma with Kussmaul breathing

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

CLINICAL CONDITION	MECHANISM	FINDINGS
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.