Pancreas

The pancreas is a long, slender organ, most of which is located posterior

to the bottom half of the stomach (Figure 1). Although it is primarily an
exocrine gland, secreting a variety of digestive enzymes, the pancreas has
an endocrine function. Its pancreatic islets—clusters of cells formerly
known as the islets of Langerhans—secrete the hormones

glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).

Pancreas. The pancreatic exocrine function involves the acinar cells secreting digestive enzymes
that are transported into the small intestine by the pancreatic duct. Its endocrine function
involves the secretion of insulin (produced by beta cells) and glucagon (produced by alpha cells)
within the pancreatic islets. These two hormones regulate the rate of glucose metabolism in the
body. The micrograph reveals pancreatic islets. LM × 760.

Cells and Secretions of the Pancreatic Islets

The pancreatic islets each contain four varieties of cells:
• The alpha cell produces the hormone glucagon and makes up approximately
20 percent of each islet. Glucagon plays an important role in blood glucose
regulation; low blood glucose levels stimulate its release.
• The beta cell produces the hormone insulin and makes up approximately 75
percent of each islet. Elevated blood glucose levels stimulate the release of
insulin.

• The delta cell accounts for four percent of the islet cells and secretes the
peptide hormone somatostatin. Somatostatin is also released by the
hypothalamus (as growth hormone–inhibiting hormone (GHIH)), and the stomach
and intestines also secrete it. An inhibiting hormone, pancreatic somatostatin
inhibits the release of both glucagon and insulin.

• The PP cell accounts for about one percent of islet cells and secretes the
pancreatic polypeptide hormone. It is thought to play a role in appetite, as well
as in the regulation of pancreatic exocrine and endocrine secretions. Pancreatic
polypeptide released following a meal may reduce further food consumption;
however, it is also released in response to fasting.

Regulation of Blood Glucose Levels by Insulin and Glucagon

Glucose is required for cellular respiration and is the preferred fuel for all body
cells. The body derives glucose from the breakdown of the carbohydrate-
containing foods and drinks we consume. Glucose not immediately taken up by
cells for fuel can be stored by the liver and muscles as glycogen, or converted to
triglycerides and stored in the adipose tissue. Hormones regulate both the storage
and the utilization of glucose as required. Receptors located in the pancreas sense
blood glucose levels, and subsequently the pancreatic cells secrete glucagon or
insulin to maintain normal levels.

Glucagon
Receptors in the pancreas can sense the decline in blood glucose levels, such as
during periods of fasting or during prolonged labor or exercise (Figure 2). In
response, the alpha cells of the pancreas secrete the hormone glucagon, which has
several effects:
• It stimulates the liver to convert its stores of glycogen back into glucose. This
response is known as glycogenolysis. The glucose is then released into the
circulation for use by body cells.
• It stimulates the liver to take up amino acids from the blood and convert them
into glucose. This response is known as gluconeogenesis.
• It stimulates lipolysis, the breakdown of stored triglycerides into free fatty
acids and glycerol. Some of the free glycerol released into the bloodstream
travels to the liver, which converts it into glucose. This is also a form of
gluconeogenesis.
Taken together, these actions increase blood glucose levels. The activity of
glucagon is regulated through a negative feedback mechanism; rising blood
glucose levels inhibit further glucagon production and secretion.
Homeostatic Regulation of Blood Glucose Levels. Blood glucose concentration is tightly
maintained between 70 mg/dL and 110 mg/dL. If blood glucose concentration rises above this
range, insulin is released, which stimulates body cells to remove glucose from the blood. If blood
glucose concentration drops below this range, glucagon is released, which stimulates body cells
to release glucose into the blood.

Insulin
The primary function of insulin is to facilitate the uptake of glucose into
body cells. Red blood cells, as well as cells of the brain, liver, kidneys, and
the lining of the small intestine, do not have insulin receptors on their cell
membranes and do not require insulin for glucose uptake. Although all
other body cells do require insulin if they are to take glucose from the
bloodstream, skeletal muscle cells and adipose cells are the primary targets
of insulin.
The presence of food in the intestine triggers the release of gastrointestinal
tract hormones such as glucose-dependent insulinotropic peptide
(previously known as gastric inhibitory peptide). This is in turn the initial
trigger for insulin production and secretion by the beta cells of the
pancreas. Once nutrient absorption occurs, the resulting surge in blood
glucose levels further stimulates insulin secretion.
Precisely how insulin facilitates glucose uptake is not entirely clear.
However, insulin appears to activate a tyrosine kinase receptor, triggering
the phosphorylation of many substrates within the cell. These multiple
biochemical reactions converge to support the movement of intracellular
vesicles containing facilitative glucose transporters to the cell membrane.
In the absence of insulin, these transport proteins are normally recycled
slowly between the cell membrane and cell interior. Insulin triggers the
rapid movement of a pool of glucose transporter vesicles to the cell
membrane, where they fuse and expose the glucose transporters to the
extracellular fluid. The transporters then move glucose by facilitated
diffusion into the cell interior.
Insulin also reduces blood glucose levels by stimulating glycolysis, the
metabolism of glucose for generation of ATP. Moreover, it stimulates the
liver to convert excess glucose into glycogen for storage, and it inhibits
enzymes involved in glycogenolysis and gluconeogenesis. Finally, insulin
promotes triglyceride and protein synthesis. The secretion of insulin is
regulated through a negative feedback mechanism. As blood glucose levels
decrease, further insulin release is inhibited. The pancreatic hormones are
summarized in Table 7.

Hormones of the Pancreas (Table 7)

Associated hormones Chemical class Effect

Insulin (beta cells) Protein Reduces blood glucose levels

Glucagon (alpha cells) Protein Increases blood glucose levels

Somatostatin (delta cells) Protein Inhibits insulin and glucagon release

Pancreatic polypeptide (PP cells) Protein Role in appetite

Disorders of the…
Endocrine System: Diabetes Mellitus
Dysfunction of insulin production and secretion, as well as the target cells’
responsiveness to insulin, can lead to a condition called diabetes
mellitus. An increasingly common disease, diabetes mellitus has been
diagnosed in more than 18 million adults in the United States, and more
than 200,000 children. It is estimated that up to 7 million more adults have
the condition but have not been diagnosed. In addition, approximately 79
million people in the US are estimated to have pre-diabetes, a condition in
which blood glucose levels are abnormally high, but not yet high enough to
be classified as diabetes.
There are two main forms of diabetes mellitus. Type 1 diabetes is an
autoimmune disease affecting the beta cells of the pancreas. Certain genes
are recognized to increase susceptibility. The beta cells of people with type 1
diabetes do not produce insulin; thus, synthetic insulin must be
administered by injection or infusion. This form of diabetes accounts for
less than five percent of all diabetes cases.
Type 2 diabetes accounts for approximately 95 percent of all cases. It is
acquired, and lifestyle factors such as poor diet, inactivity, and the presence
of pre-diabetes greatly increase a person’s risk. About 80 to 90 percent of
people with type 2 diabetes are overweight or obese. In type 2 diabetes,
cells become resistant to the effects of insulin. In response, the pancreas
increases its insulin secretion, but over time, the beta cells become
exhausted. In many cases, type 2 diabetes can be reversed by moderate
weight loss, regular physical activity, and consumption of a healthy diet;
however, if blood glucose levels cannot be controlled, the diabetic will
eventually require insulin.
Two of the early manifestations of diabetes are excessive urination and
excessive thirst. They demonstrate how the out-of-control levels of glucose
in the blood affect kidney function. The kidneys are responsible for filtering
glucose from the blood. Excessive blood glucose draws water into the urine,
and as a result the person eliminates an abnormally large quantity of sweet
urine. The use of body water to dilute the urine leaves the body dehydrated,
and so the person is unusually and continually thirsty. The person may also
experience persistent hunger because the body cells are unable to access the
glucose in the bloodstream.

Over time, persistently high levels of glucose in the blood injure tissues
throughout the body, especially those of the blood vessels and nerves.
Inflammation and injury of the lining of arteries lead to atherosclerosis and
an increased risk of heart attack and stroke. Damage to the microscopic
blood vessels of the kidney impairs kidney function and can lead to kidney
failure. Damage to blood vessels that serve the eyes can lead to blindness.
Blood vessel damage also reduces circulation to the limbs, whereas nerve
damage leads to a loss of sensation, called neuropathy, particularly in the
hands and feet. Together, these changes increase the risk of injury,
infection, and tissue death (necrosis), contributing to a high rate of toe,
foot, and lower leg amputations in people with diabetes. Uncontrolled
diabetes can also lead to a dangerous form of metabolic acidosis called
ketoacidosis. Deprived of glucose, cells increasingly rely on fat stores for
fuel. However, in a glucose-deficient state, the liver is forced to use an
alternative lipid metabolism pathway that results in the increased
production of ketone bodies (or ketones), which are acidic. The build-up of
ketones in the blood causes ketoacidosis, which—if left untreated—may lead
to a life-threatening “diabetic coma.” Together, these complications make
diabetes the seventh leading cause of death in the United States.
Diabetes is diagnosed when lab tests reveal that blood glucose levels are
higher than normal, a condition called hyperglycemia. The treatment of
diabetes depends on the type, the severity of the condition, and the ability
of the patient to make lifestyle changes. As noted earlier, moderate weight
loss, regular physical activity, and consumption of a healthful diet can
reduce blood glucose levels. Some patients with type 2 diabetes may be
unable to control their disease with these lifestyle changes, and will require
medication. Historically, the first-line treatment of type 2 diabetes was
insulin. Research advances have resulted in alternative options, including
medications that enhance pancreatic function.