ANATOMY AND PHYSIOLOGY

The Endocrine Pancreas

The pancreas is a long, slender organ that is mostly located posterior to the
stomach's bottom half (Figure 1). Although the pancreas is primarily an exocrine
gland that secretes a variety of digestive enzymes, it also serves an endocrine
function. Its pancreatic islets—cell clusters formerly known as Langerhans islets—
secrete the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide
(PP).
1st Figure The pancreatic exocrine function involves acinar cells secreting
digestive enzymes, which are then transported into the small intestine by the
pancreatic duct. Its endocrine function entails the secretion of insulin (by beta cells)
and glucagon (by alpha cells) within the pancreatic islets. These two hormones
control the rate at which glucose is metabolized in the body. Pancreatic islets can
be seen in the micrograph. LM 760 is an abbreviation for the letter LM.
(Micrograph provided by the University of Michigan Medical School Regents in
2012)

Cells and Secretions of the Pancreatic Islets

The pancreatic islets each contain four varieties of cells:

 The alpha cell, which accounts for approximately 20% of each islet, produces the
hormone glucagon. Low blood glucose levels stimulate the release of glucagon,
which plays an important role in blood glucose regulation.

 The beta cell, which accounts for approximately 75% of each islet, produces the
hormone insulin. Elevated blood glucose levels cause insulin to be released.

 The delta cell makes up 4% of islet cells and secretes the peptide hormone
somatostatin. Remember that somatostatin is also secreted by the hypothalamus
(as GHIH) and the stomach and intestines. Pancreatic somatostatin is an
inhibiting hormone that inhibits the release of both glucagon and insulin.

 The pancreatic polypeptide hormone is secreted by the PP cell, which accounts

for about 1% of islet cells. It is thought to play a role in appetite regulation as
well as pancreatic exocrine and endocrine secretion regulation. Although
pancreatic polypeptide released after a meal may reduce subsequent food
consumption, it is also released in response to fasting.

Regulation of Blood Glucose Levels by Insulin and Glucagon

Glucose is the preferred fuel for all body cells and is required for cellular
respiration. The breakdown of carbohydrate-containing foods and beverages provides
glucose to the body. Glucose that is not immediately taken up by cells for fuel can be
stored as glycogen by the liver and muscles, or converted to triglycerides and stored
in adipose tissue. Hormones control both the storage and utilization of glucose as
needed. Pancreatic receptors detect blood glucose levels, and pancreatic cells secrete
glucagon or insulin to maintain normal levels.

Glucagon
Pancreatic receptors can detect a drop in blood glucose levels, such as during
fasting or prolonged labor or exercise (Figure 2). In response, pancreatic alpha cells
secrete the hormone glucagon, which has several effects:

 It stimulates the liver to convert glycogen stores back into glucose. This is
referred to as glycogenolysis. The glucose is then released into the bloodstream
for use by the body's cells.

 It causes the liver to absorb amino acids from the blood and convert them to
glucose. This is referred to as gluconeogenesis.

 It promotes lipolysis, which is the breakdown of triglycerides into free fatty acids
and glycerol. Some of the free glycerol released into the bloodstream is converted
into glucose by the liver. This is a type of gluconeogenesis as well.

These actions, when combined, raise blood glucose levels. A negative feedback
mechanism regulates glucagon activity; rising blood glucose levels inhibit further
glucagon production and secretion.

Figure 2 is a diagram. The

blood glucose concentration is
tightly controlled between 70
and 110 mg/dL. If blood
glucose levels rise above this
threshold, insulin is released,
stimulating body cells to
remove glucose from the blood.
If blood glucose levels fall
below this level, glucagon is
released, which stimulates body
cells to release glucose into the
blood.

Insulin
Insulin's primary function is to facilitate glucose uptake into body cells. Red
blood cells, as well as brain, liver, kidney, and small intestine lining cells, lack insulin
receptors on their cell membranes and do not require insulin for glucose uptake.
Although all other body cells require insulin to take glucose from the bloodstream,
skeletal muscle cells and adipose cells are insulin's primary targets.

Food in the intestine causes the release of gastrointestinal tract hormones such
as glucose-dependent insulinotropic peptide (previously known as gastric inhibitory
peptide). This, in turn, is the initial trigger for insulin production and secretion by
pancreatic beta cells. When nutrients are absorbed, the resulting increase in blood
glucose levels stimulates insulin secretion even more.

It's not entirely clear how insulin promotes glucose uptake. Insulin, on the
other hand, appears to activate a tyrosine kinase receptor, causing the phosphorylation
of numerous substrates within the cell. These various biochemical reactions work
together to help intracellular vesicles containing facilitative glucose transporters move
to the cell membrane. These transport proteins are normally recycled slowly between
the cell membrane and the cell interior in the absence of insulin. Insulin causes a pool
of glucose transporter vesicles to rapidly move to the cell membrane, where they fuse
and expose the glucose transporters to extracellular fluid. Glucose is then transported
into the cell via facilitated diffusion by the transporters.

Insulin also lowers blood glucose levels by stimulating glycolysis, which is the
breakdown of glucose to produce ATP. Furthermore, it stimulates the liver to convert
excess glucose into glycogen for storage and inhibits glycogenolysis and
gluconeogenesis enzymes. Finally, insulin stimulates the synthesis of triglycerides
and proteins. Insulin secretion is controlled by a negative feedback mechanism.
Further insulin release is inhibited as blood glucose levels fall. Table 1 summarizes
the pancreatic hormones.

Table 1. Hormones of the Pancreas

ASSOCIATED CHEMICAL CLASS EFFECT
HORMONES
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 Protein Role in appetite
( PP ceslls)

DISORDERS OF ENDOCRINE SYSTEM

Diabetes Mellitus
Diabetes mellitus is caused by a malfunction in insulin production and
secretion, as well as the responsiveness of target cells to insulin. Diabetes mellitus, an
increasingly common disease, has been diagnosed in more than 18 million adults and
more than 200,000 children in the United States. Up to 7 million more adults are
thought to have the condition but have not been diagnosed. Furthermore, it is
estimated that 79 million people in the United States have pre-diabetes, a condition in
which blood glucose levels are abnormally high but not high enough to be classified
as diabetes.
Diabetes mellitus is classified into two types. Type 1 diabetes is an
autoimmune disease that affects the pancreatic beta cells. Certain genes have been
identified as increasing susceptibility. Because type 1 diabetes patients' beta cells do
not produce insulin, synthetic insulin must be administered via injection or infusion.
This type of diabetes accounts for less than 5% of all cases of diabetes.
Type 2 diabetes accounts for roughly 95% of all cases. It is acquired, and
lifestyle factors such as poor diet, inactivity, and the presence of pre-diabetes increase
a person's risk significantly. Approximately 80–90% of people with type 2 diabetes
are overweight or obese. Cells become resistant to the effects of insulin in type 2
diabetes. In response, the pancreas increases insulin secretion, but beta cells become
exhausted over time. Type 2 diabetes can often be reversed with moderate weight
loss, regular physical activity, and a healthy diet; however, if blood glucose levels are
not controlled, the diabetic will eventually require insulin.
Excessive urination and thirst are two of the first symptoms of diabetes. They
show how out-of-control glucose levels in the blood affect kidney function. The
kidneys are in charge of removing glucose from the blood. Excessive blood glucose
draws water into the urine, causing the person to excrete an abnormally large amount
of sweet urine. The use of body water to dilute urine dehydrates the body, causing the
person to be unusually and constantly thirsty. Because the body cells are unable to
access the glucose in the bloodstream, the person may experience persistent hunger.
Persistently high levels of glucose in the blood cause damage to tissues
throughout the body, particularly those of the blood vessels and nerves.
Atherosclerosis is caused by inflammation and injury to the lining of the arteries, as
well as an increased risk of heart attack and stroke. Damage to the kidney's
microscopic blood vessels impairs kidney function and can lead to kidney failure.
Damage to the blood vessels that supply the eyes can result in blindness. Blood vessel
damage also reduces circulation to the limbs, whereas nerve damage causes
neuropathy, or a loss of sensation, particularly in the hands and feet. These changes,
when combined, increase the risk of injury, infection, and tissue death (necrosis),
contributing to a high rate of toe, foot, and lower leg amputations in diabetics.
Uncontrolled diabetes can also result in ketoacidosis, a dangerous form of metabolic
acidosis. When cells are deprived of glucose, they increasingly rely on fat stores for
fuel. In a glucose-deficient state, however, the liver is forced to use an alternative
lipid metabolism pathway, which results in an increase in the production of acidic
ketone bodies (or ketones). Ketoacidosis is caused by a buildup of ketones in the
blood, which can lead to a life-threatening "diabetic coma" if left untreated. Diabetes
is the seventh leading cause of death in the United States due to these complications.
Diabetes is diagnosed when blood glucose levels are higher than normal, a
condition known as hyperglycemia. Diabetes treatment is determined by the type of
diabetes, the severity of the condition, and the patient's ability to make lifestyle
changes. As previously stated, moderate weight loss, regular physical activity, and a
healthy diet can all help to lower blood glucose levels. Some type 2 diabetes patients
may be unable to control their disease with lifestyle changes alone and will require
medication.Historically, insulin was the first-line treatment for type 2 diabetes.
Alternative options, such as medications that improve pancreatic function, have
emerged as a result of research advances.

SUMMARY:
 Exocrine and endocrine functions are performed by the pancreas. Alpha cells,
which produce glucagon, beta cells, which produce insulin, delta cells, which produce
somatostatin, and PP cells, which produce pancreatic polypeptide are all types of
pancreatic islet cells. Insulin and glucagon are hormones that regulate glucose
metabolism. In response to high blood glucose levels, beta cells produce insulin. It
improves glucose uptake and utilization by target cells, as well as glucose storage for
later use.Diabetes mellitus is a disorder characterized by high blood glucose levels
caused by a malfunction in insulin production or target cell resistance to the effects of
insulin. In response to low blood glucose levels, the pancreatic alpha cells produce
and secrete the hormone glucagon. Glucagon stimulates mechanisms that raise blood
glucose levels, such as glycogen catabolism into glucose.

VI. PATHOPHYSIOLOGY
As we learn more about the pathophysiology of diabetes mellitus, we find that
there is more yet to be discovered. Diabetes mellitus is a syndrome with
disordered metabolism and inappropriate hyperglycemia due to either a
deficiency of insulin secretion or to a combination of insulin resistance and
inadequate insulin secretion to compensate. Type 1 diabetes is due to pancreatic
islet B cell destruction predominantly by an autoimmune process, and these
persons are prone to ketoacidosis. While type 2 diabetes is the more prevalent
form and results from insulin resistance with a defect in compensatory insulin
secretion. Diabetes can lead to serious complications, resulting in multiple
diseases or disorders that affect multiple systems that may result in premature
death.
Normal Pathology of the Human Body
In people that are healthy, the pancreas, an organ located behind the liver and
stomach, secretes digestive enzymes and the hormones insulin and glucagon into
the bloodstream to control the amount of glucose in the body. The release of
insulin into the blood lowers the level of blood glucose (simple sugars from
food) by allowing glucose to enter the body cells, where it is metabolized. If
blood glucose levels get too low, the pancreas secretes glucagon to stimulate the
release of glucose from the liver. Right after a meal, glucose and amino acids are
absorbed directly into the bloodstream, and blood glucose levels rise sharply.
The rise in blood glucose levels signals important cells in the pancreas, called
beta cells, to secrete insulin, which pours into the bloodstream. Within 20
minutes after a meal insulin rises to its peak level.
Insulin enables glucose to enter cells in the body, particularly muscle and liver
cells. Here, insulin and other hormones direct whether glucose will be burned for
energy or stored for future use. When insulin levels are high, the liver stops
producing glucose and stores it in other forms until the body needs it again. As
blood glucose levels reach their peak, the pancreas reduces the production of
insulin (about 2 - 4 hours after a meal both blood glucose and insulin are at low
levels).

Type 1 Diabetes
Type 1 diabetes is usually diagnosed in children and young adults. It develops
when the body’s immune system destroys pancreatic beta cells, the only cells in
the body that make the hormone insulin, which regulates blood glucose.

Only 5% of people with diabetes have this form of the disease. To survive,
people with type 1 diabetes must have insulin delivered by injection or a pump.

Type 2 Diabetes
Type 2 diabetes is the most common form of diabetes. The causes of type 2
diabetes are multi-factorial and include both genetic and environmental elements
that affect beta-cell function and tissue (muscle, liver, adipose tissue, and
pancreas) insulin sensitivity. In type 2 diabetes, either the body does not produce
enough insulin or the cells ignore the insulin. It usually begins as insulin
resistance, a disorder in which the cells do not use insulin properly. As the need
for insulin rises, the pancreas gradually loses its ability to produce it.

When glucose builds up in the blood instead of going into cells, it can cause far-
reaching health implications like heart disease, nerve damage and kidney
damage. Diabetes is the leading cause of kidney failure, non-traumatic lower-
limb amputations, and new cases of blindness among adults in the United States.

You can prevent or delay the onset of type 2 diabetes through a healthy lifestyle
such as changing your diet , increasing your level of physical activity,
maintaining a healthy weight... with these positive steps, you can stay healthier
longer and reduce your risk of diabetes.
Introduction
Diabetes Mellitus is a serious disease that occurs when the body has difficulty
properly regulating the amount of dissolved sugar (glucose) in the blood stream. It is
unrelated to a similarly named disorder "Diabetes Insipidus" which involves kidney-
related fluid retention problems. In order to understand diabetes, it is necessary to first
understand the role glucose plays with regard to the body, and what can happen when
regulation of glucose fails and blood sugar levels become dangerously low or high.
The tissues and cells that make up the human body are living things, and
require food to stay alive. The food cells eat is a type of sugar called glucose. Fixed in
place as they are, the body's cells are completely dependent on the blood stream in
which they are bathed to bring glucose to them. Without access to adequate glucose,
the body's cells have nothing to fuel themselves with and soon die. Human beings eat
food, not glucose. Human foods get converted into glucose as a part of the normal
digestion process. Once converted, glucose enters the blood stream, causing the level
of dissolved glucose inside the blood to rise. The blood stream then carries the
dissolved glucose to the various tissues and cells of the body.
 Though glucose may be available in the blood, nearby cells are not able to
access that glucose without the aid of a chemical hormone called insulin. Insulin acts
as a key to open the cells, allowing them to receive and utilize available glucose. Cells
absorb glucose from the blood in the presence of insulin, and blood sugar levels drop
as sugar leaves the blood and enters the cells. Insulin can be thought of as a bridge for
glucose between the blood stream and cells. It is important to understand when levels
of insulin increase, levels of sugar in the blood decrease with the reason that the sugar
goes into the cells to be used for energy. The body is designed to regulate and buffer
the amount of glucose dissolved in the blood to maintain a steady supply to meet cell
needs. The pancreas, one of the body's many organs, produces, stores and releases
insulin into the blood stream to bring glucose levels back down.

The concentration of glucose available in the blood stream at any given

moment is dependent on the amount and type of foods that people eat. Refined
carbohydrates, candy and sweets are easy to break down into glucose.
Correspondingly, blood glucose levels rise rapidly after such foods have been eaten.
In contrast, blood sugars rise gradually and slowly after eating more complex,
unrefined carbohydrates (oatmeal, apples, baked potatoes, etc.) which require more
digestive steps take place before glucose can be yielded. Faced with rapidly rising
blood glucose concentrations, the body must react quickly by releasing large amounts
of insulin all at once or risk a dangerous condition called Hyperglycemia (high blood
sugar) which will be described below.

The influx of insulin enables cells to utilize glucose, and glucose

concentrations drop. While glucose levels can rise and fall rapidly, insulin levels
change much more slowly.  When a large amount of simple sugar is eaten the
bloodstream quickly becomes flooded with glucose.  Insulin is released by the
pancreas in response to the increased sugar.  The glucose rapidly enters the cells but
the high levels of insulin remain in the bloodstream for a period of time.  This can
result in an overabundance of insulin in the blood, which can trigger feelings of
hunger and even Hypoglycemia (low blood sugar), another serious condition.

When blood glucose concentrations rise more gradually, there is less need for
dramatic compensation. Insulin can be released in a more controlled and safer manner
which requires the body experience less strain. This more gradual process will leave
feeling “full” or content for a longer period of time. For these reasons, it is best for
overall health to limit the amount and frequency of sweets and refined sugars in the
diet. Instead eat more complex sugars such as raw fruit, whole wheat bread and pasta,
and beans. The difference between simple and complex sugars (carbohydrates) is
exemplified by the difference between white (simple) and whole wheat (more
complex) bread.

Insulin is the critical key to the cell's ability to use glucose. Problems with
insulin production or with how insulin is recognized by the cells can easily cause the
body's carefully balanced glucose metabolism system to get out of control. When
either of these problems occur, Diabetes develops, blood sugar levels surge and crash
and the body risks becoming damaged.

MEDICATIONS
glicazide 60mg mg every morning before breakfast
atorvastatin (Lipitor), 10 mg daily
Metformin 500mg 1 tablet BID
Amlodipine 10mg 1 tab OD in the afternoon
Losartan 50mg 1 tab OD in am
Clopidogrel 100mg 1 tab OD after meal