Diabetes Mellitus

Medical Author: Ruchi Mathur, MD

Medical Editor: William C. Shiel, Jr., MD, FACP, FACR

• What is diabetes?
• What is the impact of diabetes?
• What causes diabetes?
• What are the different types of diabetes?
• What are diabetes symptoms?
• How is diabetes diagnosed?
• Why is blood sugar checked at home?
• What are the acute complications of diabetes?
• What are the chronic complications of diabetes?
• What can be done to slow diabetes complications?

Diabetes At A Glance

What is diabetes?

Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar (glucose) levels,
that result from defects in insulin secretion, or action, or both. Diabetes mellitus, commonly referred to
as diabetes (as it will be in this article) was first identified as a disease associated with "sweet urine,"
and excessive muscle loss in the ancient world. Elevated levels of blood glucose (hyperglycemia) lead
to spillage of glucose into the urine, hence the term sweet urine.

Normally, blood glucose levels are tightly controlled by insulin, a hormone produced by the pancreas.
Insulin lowers the blood glucose level. When the blood glucose elevates (for example, after eating
food), insulin is released from the pancreas to normalize the glucose level. In patients with diabetes,
the absence or insufficient production of insulin causes hyperglycemia. Diabetes is a chronic medical
condition, meaning that although it can be controlled, it lasts a lifetime.

What is the impact of diabetes?

Over time, diabetes can lead to blindness, kidney failure, and nerve damage. These types of damage
are the result of damage to small vessels, referred to as microvascular disease. Diabetes is also an
important factor in accelerating the hardening and narrowing of the arteries (atherosclerosis), leading
to strokes, coronary heart disease, and other large blood vessel diseases. This is referred to as
macrovascular disease. Diabetes affects approximately 17 million people (about 8% of the population)
in the United States. In addition, an estimated additional 12 million people in the United States have
diabetes and don't even know it.

From an economic perspective, the total annual cost of diabetes in 1997 was estimated to be 98 billion
dollars in the United States. The per capita cost resulting from diabetes in 1997 amounted to
$10,071.00; while healthcare costs for people without diabetes incurred a per capita cost of $2,699.00.
During this same year, 13.9 million days of hospital stay were attributed to diabetes, while 30.3
million physician office visits were diabetes related. Remember, these numbers reflect only the
population in the United States. Globally, the statistics are staggering.

Diabetes is the third leading cause of death in the United States after heart disease and cancer.

What causes diabetes?

Insufficient production of insulin (either absolutely or relative to the body's needs), production of
defective insulin (which is uncommon), or the inability of cells to use insulin properly and efficiently
leads to hyperglycemia and diabetes. This latter condition affects mostly the cells of muscle and fat
tissues, and results in a condition known as "insulin resistance." This is the primary problem in type 2
diabetes. The absolute lack of insulin, usually secondary to a destructive process affecting the insulin
producing beta cells in the pancreas, is the main disorder in type 1 diabetes. In type 2 diabetes, there
also is a steady decline of beta cells that adds to the process of elevated blood sugars. Essentially, if
someone is resistant to insulin, the body can, to some degree, increase production of insulin and
overcome the level of resistance. After time, if production decreases and insulin cannot be released as
vigorously, hyperglycemia develops.

Glucose is a simple sugar found in food. Glucose is an essential nutrient that provides energy for the
proper functioning of the body cells. Carbohydrates are broken down in the small intestine and the
glucose in digested food is then absorbed by the intestinal cells into the bloodstream, and is carried by
the bloodstream to all the cells in the body where it is utilized. However, glucose cannot enter the cells
alone and needs insulin to aid in its transport into the cells. Without insulin, the cells become starved
of glucose energy despite the presence of abundant glucose in the bloodstream. In certain types of
diabetes, the cells' inability to utilize glucose gives rise to the ironic situation of "starvation in the
midst of plenty". The abundant, unutilized glucose is wastefully excreted in the urine.

Insulin is a hormone that is produced by specialized cells (beta cells) of the pancreas. (The pancreas is
a deep-seated organ in the abdomen located behind the stomach.) In addition to helping glucose enter
the cells, insulin is also important in tightly regulating the level of glucose in the blood. After a meal,
the blood glucose level rises. In response to the increased glucose level, the pancreas normally releases
more insulin into the bloodstream to help glucose enter the cells and lower blood glucose levels after a
meal. When the blood glucose levels are lowered, the insulin release from the pancreas is turned down.
It is important to note that even in the fasting state there is a low steady release of insulin than
fluctuates a bit and helps to maintain a steady blood sugar level during fasting. In normal individuals,
such a regulatory system helps to keep blood glucose levels in a tightly controlled range. As outlined
above, in patients with diabetes, the insulin is either absent, relatively insufficient for the body's needs,
or not used properly by the body. All of these factors cause elevated levels of blood glucose
(hyperglycemia).
What are the different types of diabetes?

There are two major types of diabetes, called type 1 and type 2. Type 1 diabetes was also called insulin
dependent diabetes mellitus (IDDM), or juvenile onset diabetes mellitus. In type 1 diabetes, the
pancreas undergoes an autoimmune attack by the body itself, and is rendered incapable of making
insulin. Abnormal antibodies have been found in the majority of patients with type 1 diabetes.
Antibodies are proteins in the blood that are part of the body's immune system. The patient with type 1
diabetes must rely on insulin medication for survival.

In autoimmune diseases, such as type 1 diabetes, the immune system mistakenly manufactures
antibodies and inflammatory cells that are directed against and cause damage to patients' own body
tissues. In persons with type 1 diabetes, the beta cells of the pancreas, which are responsible for insulin
production, are attacked by the misdirected immune system. It is believed that the tendency to develop
abnormal antibodies in type 1 diabetes is, in part, genetically inherited, though the details are not fully
understood.

Exposure to certain viral infections (mumps and Coxsackie viruses) or other environmental toxins may
serve to trigger abnormal antibody responses that cause damage to the pancreas cells where insulin is
made. Some of the antibodies seen in type 1 diabetes include anti-islet cell antibodies, anti-insulin
antibodies and anti-glutamic decarboxylase antibodies. These antibodies can be measured in the
majority of patients, and may help determine which individuals are at risk for developing type 1
diabetes.

At present, the American Diabetes Association does not recommend general screening of the
population for type 1 diabetes, though screening of high risk individuals, such as those with a first
degree relative (sibling or parent) with type 1 diabetes should be encouraged. Type 1 diabetes tends to
occur in young, lean individuals, usually before 30 years of age, however, older patients do present
with this form of diabetes on occasion. This subgroup is referred to as latent autoimmune diabetes in
adults (LADA). LADA is a slow, progressive form of type 1 diabetes. Of all the patients with diabetes,
only approximately 10% of the patients have type 1 diabetes and the remaining 90% have type 2
diabetes.

Type 2 diabetes was also referred to as non-insulin dependent diabetes mellitus (NIDDM), or adult
onset diabetes mellitus (AODM). In type 2 diabetes, patients can still produce insulin, but do so
relatively inadequately for their body's needs, particularly in the face of insulin resistance as discussed
above. In many cases this actually means the pancreas produces larger than normal quantities of
insulin. A major feature of type 2 diabetes is a lack of sensitivity to insulin by the cells of the body
(particularly fat and muscle cells).

In addition to the problems with an increase in insulin resistance, the release of insulin by the pancreas
may also be defective and suboptimal. In fact, there is a known steady decline in beta cell production
of insulin in type 2 diabetes that contributes to worsening glucose control. (This is a major factor for
many patients with type 2 diabetes who ultimately require insulin therapy.) Finally, the liver in these
patients continues to produce glucose through a process called gluconeogenesis despite elevated
glucose levels. The control of gluconeogenesis becomes compromised.

While it is said that type 2 diabetes occurs mostly in individuals over 30 years old and the incidence
increases with age, we are seeing an alarming number patients with type 2 diabetes who are barely in
their teen years. In fact, for the first time in the history of humans, type 2 diabetes is now more
common than type 1 diabetes in childhood. Most of these cases are a direct result of poor eating habits,
higher body weight, and lack of exercise.

While there is a strong genetic component to developing this form of diabetes, there are other risk
factors - the most significant of which is obesity. There is a direct relationship between the degree of
obesity and the risk of developing type 2 diabetes, and this holds true in children as well as adults. It is
estimated that the chance to develop diabetes doubles for every 20% increase over desirable body
weight.

Regarding age, data shows that for each decade after 40 years of age regardless of weight there is an
increase in incidence of diabetes. The prevalence of diabetes in persons 65 to 74 years of age is nearly
20%. Type 2 diabetes is also more common in certain ethnic groups. Compared with a 6% prevalence
in Caucasians, the prevalence in African Americans and Asian Americans is estimated to be 10%, in
Hispanics 15%, and in certain Native American communities 20% to 50%. Finally, diabetes occurs
much more frequently in women with a prior history of diabetes that develops during pregnancy
(gestational diabetes - see below).

Diabetes can occur temporarily during pregnancy. Significant hormonal changes during pregnancy can
lead to blood sugar elevation in genetically predisposed individuals. Blood sugar elevation during
pregnancy is called gestational diabetes. Gestational diabetes usually resolves once the baby is born.
However, 25%-50% of women with gestational diabetes will eventually develop type 2 diabetes later
in life, especially in those who require insulin during pregnancy and those who remain overweight
after their delivery. Patients with gestational diabetes are usually asked to undergo an oral glucose
tolerance test about six weeks after giving birth to determine if their diabetes has persisted beyond the
pregnancy, or if any evidence (such as impaired glucose tolerance) is present that may be a clue to the
patient's future risk for developing diabetes.

"Secondary" diabetes refers to elevated blood sugar levels from another medical condition. Secondary
diabetes may develop when the pancreatic tissue responsible for the production of insulin is destroyed
by disease, such as chronic pancreatitis (inflammation of the pancreas by toxins like excessive
alcohol), trauma, or surgical removal of the pancreas.

Diabetes can also result from other hormonal disturbances, such as excessive growth hormone
production (acromegaly) and Cushing's syndrome. In acromegaly, a pituitary gland tumor at the base
of the brain causes excessive production of growth hormone, leading to hyperglycemia. In Cushing's
syndrome, the adrenal glands produce an excess of cortisol, which promotes blood sugar elevation.

In addition, certain medications may worsen diabetes control, or "unmask" latent diabetes. This is seen
most commonly when steroid medications (such as prednisone) are taken and also with medications
used in the treatment of HIV infection (AIDS).

What are diabetes symptoms?

• The early symptoms of untreated diabetes are related to elevated blood sugar levels, and loss of
glucose in the urine. High amounts of glucose in the urine can cause increased urine output and
lead to dehydration. Dehydration causes increased thirst and water consumption.

• The inability of insulin to perform normally has effects on protein, fat and carbohydrate
metabolism. Insulin is an anabolic hormone, that is, one that encourages storage of fat and
protein.

• A relative or absolute insulin deficiency eventually leads to weight loss despite an increase in
appetite.

• Some untreated diabetes patients also complain of fatigue, nausea and vomiting.

• Patients with diabetes are prone to developing infections of the bladder, skin, and vaginal
areas.

• Fluctuations in blood glucose levels can lead to blurred vision. Extremely elevated glucose
levels can lead to lethargy and coma.

How is diabetes diagnosed?

The fasting blood glucose (sugar) test is the preferred way to diagnose diabetes. It is easy to perform
and convenient. After the person has fasted overnight (at least 8 hours), a single sample of blood is
drawn and sent to the laboratory for analysis. This can also be done accurately in a doctor's office
using a glucose meter.

• Normal fasting plasma glucose levels are less than 100 milligrams per deciliter (mg/dl).
 • Fasting plasma glucose levels of more than 126 mg/dl on two or more tests on different days
indicate diabetes.

• A random blood glucose test can also be used to diagnose diabetes. A blood glucose level of
200 mg/dl or higher indicates diabetes.

When fasting blood glucose stays above 100mg/dl, but in the range of 100-126mg/dl, this is known as
impaired fasting glucose (IFG). While patients with IFG do not have the diagnosis of diabetes, this
condition carries with it its own risks and concerns, and is addressed elsewhere.

The oral glucose tolerance test

Though not routinely used anymore, the oral glucose tolerance test (OGTT) is a gold standard for
making the diagnosis of type 2 diabetes. It is still commonly used for diagnosing gestational diabetes
and in conditions of pre-diabetes, such as polycystic ovary syndrome. With an oral glucose tolerance
test, the person fasts overnight (at least eight but not more than 16 hours). Then first, the fasting
plasma glucose is tested. After this test, the person receives 75 grams of glucose (100 grams for
pregnant women). There are several methods employed by obstetricians to do this test, but the one
described here is standard. Usually, the glucose is in a sweet-tasting liquid that the person drinks.
Blood samples are taken at specific intervals to measure the blood glucose.

For the test to give reliable results:

• the person must be in good health (not have any other illnesses, not even a cold).

• the person should be normally active (not lying down, for example, as an inpatient in a
hospital), and

• the person should not be taking medicines that could affect the blood glucose.

• For three days before the test, the person should have eaten a diet high in carbohydrates (200-
300 grams per day).

• The morning of the test, the person should not smoke or drink coffee.

The classic oral glucose tolerance test measures blood glucose levels five times over a period of three
hours. Some physicians simply get a baseline blood sample followed by a sample two hours after
drinking the glucose solution. In a person without diabetes, the glucose levels rise and then fall
quickly. In someone with diabetes, glucose levels rise higher than normal and fail to come back down
as fast.

People with glucose levels between normal and diabetic have impaired glucose tolerance (IGT).
People with impaired glucose tolerance do not have diabetes, but are at high risk for progressing to
diabetes. Each year, 1%-5% of people whose test results show impaired glucose tolerance actually
eventually develop diabetes. Weight loss and exercise may help people with impaired glucose
tolerance return their glucose levels to normal. In addition, some physicians advocate the use of
medications, such as metformin (Glucophage), to help prevent/delay the onset of overt diabetes.
Recent studies have shown that impaired glucose tolerance itself may be a risk factor for the
development of heart disease. In the medical community, most physicians are now understanding that
impaired glucose tolerance is nor simply a precursor of diabetes, but is its own clinical disease entity
that requires treatment and monitoring.

Evaluating the results of the oral glucose tolerance test

Glucose tolerance tests may lead to one of the following diagnoses:

• Normal response: A person is said to have a normal response when the 2-hour glucose level is
less than 140 mg/dl, and all values between 0 and 2 hours are less than 200 mg/dl.

• Impaired glucose tolerance: A person is said to have impaired glucose tolerance when the
fasting plasma glucose is less than 126 mg/dl and the 2-hour glucose level is between 140 and
199 mg/dl.

• Diabetes: A person has diabetes when two diagnostic tests done on different days show that
the blood glucose level is high.

• Gestational diabetes: A woman has gestational diabetes when she has any two of the
following: a 100g OGTT, a fasting plasma glucose of more than 95 mg/dl, a 1-hour glucose
level of more than 180 mg/dl, a 2-hour glucose level of more than 155 mg/dl, or a 3-hour
glucose level of more than 140 mg/dl.

Why is blood sugar checked at home?

Home blood sugar (glucose) testing is an important part of controlling blood sugar. One important
goal of diabetes treatment is to keep the blood glucose levels near the normal range of 70 to 120 mg/dl
before meals and under 140 mg/dl at two hours after eating. Blood glucose levels are usually tested
before and after meals, and at bedtime. The blood sugar level is typically determined by pricking a
fingertip with a lancing device and applying the blood to a glucose meter, which reads the value. There
are many meters on the market, for example, Accu-Check Advantage, One Touch Ultra, Sure Step and
Freestyle. Each meter has its own advantages and disadvantages (some use less blood, some have a
larger digital readout, some take a shorter time to give you results, etc). The test results are then used
to help patients make adjustments in medications, diets, and physical activities.

There are some interesting developments in blood glucose monitoring. Currently, at least three
continuous glucose sensors are approved in the United States (Dexcom, Medtronic and Navigator).
The new continuous glucose sensor systems involve an implantable cannula placed just under the skin
in the abdomen or in the arm. This cannula allows for frequent sampling of blood glucose levels.
Attached to this is a transmitter that sends the data to a pager-like device. This device has a visual
screen that allows the wearer to see, not only the current glucose reading, but also the graphic trends.
In some devices, the rate of change of blood sugar is also shown. There are alarms for low and high
sugar levels. Certain models will alarm if the rate of change indicates the wearer is at risk for dropping
or rising blood glucose too rapidly. The Medtronic version is specifically designed to interface with
their insulin pumps. However, at this time the patient still must manually approve any insulin dose (the
pump cannot blindly respond to the glucose information it receives, it can only give a calculated
suggestion as to whether the wearer should give insulin, and if so, how much). All of these devices
need to be correlated to fingersticks for a few hours before they can function independently. The
devices can then provide readings for 3-5 days.

Diabetes experts feel that these blood glucose monitoring devices give patients a significant amount of
independence to manage their disease process; and they are a great tool for education as well. It is also
important to remember that these devices can be used intermittently with fingersticks. For example, a
well-controlled patient with diabetes can rely on fingerstick glucose checks a few times a day and do
well. If they become ill, if they decide to embark on a new exercise regimen, if they change their diet
and so on, they can use the sensor to supplement their fingerstick regimen, providing more information
on how they are responding to new lifestyle changes or stressors. This kind of system takes us one step
closer to closing the loop, and to the development of an artifical pancreas that senses insulin
requirements based on glucose levels and the body's needs and releases insulin accordingly - the
ultimate goal.

Hemoglobin A1c (A1c)

To explain what an hemoglobin A1c is, think in simple terms. Sugar sticks, and when it's around for a
long time, it's harder to get it off. In the body, sugar sticks too, particularly to proteins. The red blood
cells that circulate in the body live for about three months before they die off. When sugar sticks to
these cells, it gives us an idea of how much sugar is around for the preceding three months. In most
labs, the normal range is 4%-5.9 %. In poorly controlled diabetes, its 8.0% or above, and in well
controlled patients it's less than 7.0% (optimal is <6.5%). The benefits of measuring A1c is that is
gives a more reasonable and stable view of what's happening over the course of time (three months),
and the value does not bounce as much as finger stick blood sugar measurements. There is a direct
correlation between A1c levels and average blood sugar levels as follows.

While there are no guidelines to use A1c as a screening tool, it gives a physician a good idea that
someone is diabetic if the value is elevated. Right now, it is used as a standard tool to determine blood
sugar control in patients known to have diabetes.

A1c(%) Mean blood sugar (mg/dl)

6 135
7 170
8 205
9 240
10 275
11 310
12 345

The American Diabetes Association currently recommends an A1c goal of less than 7.0%. Other
Groups such as the American Association of Clinical Endocrinologists feel that an A1c of <6.5%
should be the goal.
Of interest, studies have shown that there is about a 10% decrease in relative risk for microvascular
disease for every 1% reduction in A1c. So, if a patient starts off with an A1c of 10.7 and drops to 8.2,
though there are not yet at goal, they have managed to decrease their risk of microvascular
complications by about 20%. The closer to normal the A1c, the lower the absolute risk for
microvascular complications. Data also suggests that the risk of macrovascular disease decreases by
about 24% for every 1% reduction in A1c values.

It should be mentioned here that there are a number of conditions in which an A1c value may not be
accurate. For example, with significant anemia, the red blood cell count is low, and thus the A1c is
altered. This may also be the case in sickle cell disease and other hemoglobinopathies.

What are the acute complications of diabetes?

1. Severely elevated blood sugar levels due to an actual lack of insulin or a relative deficiency of
insulin.

2. Abnormally low blood sugar levels due to too much insulin or other glucose-lowering
medications.

Insulin is vital to patients with type 1 diabetes - they cannot live with out a source of exogenous
insulin. Without insulin, patients with type 1 diabetes develop severely elevated blood sugar levels.
This leads to increased urine glucose, which in turn leads to excessive loss of fluid and electrolytes in
the urine. Lack of insulin also causes the inability to store fat and protein along with breakdown of
existing fat and protein stores. This dysregulation, results in the process of ketosis and the release of
ketones into the blood. Ketones turn the blood acidic, a condition called diabetic ketoacidosis (DKA).
Symptoms of diabetic ketoacidosis include nausea, vomiting, and abdominal pain. Without prompt
medical treatment, patients with diabetic ketoacidosis can rapidly go into shock, coma, and even death.

Diabetic ketoacidosis can be caused by infections, stress, or trauma all which may increase insulin
requirements. In addition, missing doses of insulin is also an obvious risk factor for developing
diabetic ketoacidosis. Urgent treatment of diabetic ketoacidosis involves the intravenous
administration of fluid, electrolytes, and insulin, usually in a hospital intensive care unit. Dehydration
can be very severe, and it is not unusual to need to replace 6-7 liters of fluid when a person presents in
diabetic ketoacidosis. Antibiotics are given for infections. With treatment, abnormal blood sugar
levels, ketone production, acidosis, and dehydration can be reversed rapidly, and patients can recover
remarkably well.

In patients with type 2 diabetes, stress, infection, and medications (such as corticosteroids) can also
lead to severely elevated blood sugar levels. Accompanied by dehydration, severe blood sugar
elevation in patients with type 2 diabetes can lead to an increase in blood osmolality (hyperosmolar
state). This condition can lead to coma (hyperosmolar coma). A hyperosmolar coma usually occurs in
elderly patients with type 2 diabetes. Like diabetic ketoacidosis, a hyperosmolar coma is a medical
emergency. Immediate treatment with intravenous fluid and insulin is important in reversing the
hyperosmolar state. Unlike patients with type 1 diabetes, patients with type 2 diabetes do not generally
develop ketoacidosis solely on the basis of their diabetes. Since in general, type 2 diabetes occurs in an
older population, concomitant medical conditions are more likely to exist, and these patients may
actually be sicker overall. The complication and death rates from hyperosmolar coma is thus higher
than in DKA.

Hypoglycemia means abnormally low blood sugar (glucose). In patients with diabetes, the most
common cause of low blood sugar is excessive use of insulin or other glucose-lowering medications,
to lower the blood sugar level in diabetic patients in the presence of a delayed or absent meal. When
low blood sugar levels occur because of too much insulin, it is called an insulin reaction. Sometimes,
low blood sugar can be the result of an insufficient caloric intake or sudden excessive physical
exertion.

Blood glucose is essential for the proper functioning of brain cells. Therefore, low blood sugar can
lead to central nervous system symptoms such as:

• dizziness,

• confusion,

• weakness, and

• tremors.

The actual level of blood sugar at which these symptoms occur varies with each person, but usually it
occurs when blood sugars are less than 65 mg/dl. Untreated, severely low blood sugar levels can lead
to coma, seizures, and, in the worse case scenario, irreversible brain death. At this point, the brain is
suffering from a lack of sugar, and this usually occurs somewhere around levels of <40 mg/dl.

The treatment of low blood sugar consists of administering a quickly absorbed glucose source. These
include glucose containing drinks, such as orange juice, soft drinks (not sugar-free), or glucose tablets
in doses of 15-20 grams at a time (for example, the equivalent of half a glass of juice). Even cake
frosting applied inside the cheeks can work in a pinch if patient cooperation is difficult. If the
individual becomes unconscious, glucagon can be given by intramuscular injection.

Glucagon causes the release of glucose from the liver (for example, it promotes gluconeogenesis).
Glucagon can be lifesaving and every patient with diabetes who has a history of hypoglycemia
(particularly those on insulin) should have a glucagon kit. Families and friends of those with diabetes
need to be taught how to administer glucagon, since obviously the patients will not be able to do it
themselves in an emergency situation. Another lifesaving device that should be mentioned is very
simple; a medic alert bracelet should be worn by all patients with diabetes.

What are the chronic complications of diabetes?

These diabetes complications are related to blood vessel diseases and are generally classified into
small vessel disease, such as those involving the eyes, kidneys and nerves (microvascular disease), and
large vessel disease involving the heart and blood vessels (macrovascular disease). Diabetes
accelerates hardening of the arteries (atherosclerosis) of the larger blood vessels, leading to coronary
heart disease (angina or heart attack), strokes, and pain in the lower extremities because of lack of
blood supply (claudication).
Eye Complications

The major eye complication of diabetes is called diabetic retinopathy. Diabetic retinopathy occurs in
patients who have had diabetes for at least five years. Diseased small blood vessels in the back of the
eye cause the leakage of protein and blood in the retina. Disease in these blood vessels also causes the
formation of small aneurysms (microaneurysms), and new but brittle blood vessels
(neovascularization). Spontaneous bleeding from the new and brittle blood vessels can lead to retinal
scarring and retinal detachment, thus impairing vision.

To treat diabetic retinopathy a laser is used to destroy and prevent the recurrence of the development
of these small aneurysms and brittle blood vessels. Approximately 50% of patients with diabetes will
develop some degree of diabetic retinopathy after 10 years of diabetes, and 80% of diabetics have
retinopathy after 15 years of the disease. Poor control of blood sugar and blood pressure further
aggravates eye disease in diabetes.

Cataracts and glaucoma are also more common among diabetics. It is also important to note that since
the lens of the eye lets water through, if blood sugar concentrations vary a lot, the lens of the eye will
shrink and swell with fluid accordingly. As a result, blurry vision is very common in poorly controlled
diabetes. Patients are usually discouraged from getting a new eyeglass prescription until their blood
sugar is controlled. This allows for a more accurate assessment of what kind of glasses prescription is
required.

Kidney damage

Kidney damage from diabetes is called diabetic nephropathy. The onset of kidney disease and its
progression is extremely variable. Initially, diseased small blood vessels in the kidneys cause the
leakage of protein in the urine. Later on, the kidneys lose their ability to cleanse and filter blood. The
accumulation of toxic waste products in the blood leads to the need for dialysis. Dialysis involves
using a machine that serves the function of the kidney by filtering and cleaning the blood. In patients
who do not want to undergo chronic dialysis, kidney transplantation can be considered.

The progression of nephropathy in patients can be significantly slowed by controlling high blood
pressure, and by aggressively treating high blood sugar levels. Angiotensin converting enzyme
inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs) used in treating high blood
pressure may also benefit kidney disease in diabetic patients.

Nerve damage

Nerve damage from diabetes is called diabetic neuropathy and is also caused by disease of small blood
vessels. In essence, the blood flow to the nerves is limited, leaving the nerves without blood flow, and
they get damaged or die as a result (a term known as ischemia). Symptoms of diabetic nerve damage
include numbness, burning, and aching of the feet and lower extremities. When the nerve disease
causes a complete loss of sensation in the feet, patients may not be aware of injuries to the feet, and
fail to properly protect them. Shoes or other protection should be worn as much as possible. Seemingly
minor skin injuries should be attended to promptly to avoid serious infections. Because of poor blood
circulation, diabetic foot injuries may not heal. Sometimes, minor foot injuries can lead to serious
infection, ulcers, and even gangrene, necessitating surgical amputation of toes, feet, and other infected
parts.

Diabetic nerve damage can affect the nerves that are important for penile erection, causing erectile
dysfunction (ED, impotence). Erectile dysfunction can also be caused by poor blood flow to the penis
from diabetic blood vessel disease.

Diabetic neuropathy can also affect nerves to the stomach and intestines, causing nausea, weight loss,
diarrhea, and other symptoms of gastroparesis (delayed emptying of food contents from the stomach
into the intestines, due to ineffective contraction of the stomach muscles).

The pain of diabetic nerve damage may respond to traditional treatments with:

• gabapentin (Neurontin),

• phenytoin (Dilantin),

• carbamazepine (Tegretol),

• desipramine (Norpraminine),

• amitriptyline (Elavil), or

• with topically-applied capsaicin (an extract of pepper).

Gabapentin (Neurontin), phenytoin (Dilantin), and carbamazepine (Tegretol) are medications that are
traditionally used in the treatment of seizure disorders. Amitriptyline (Elavil) and desipramine
(Norpraminine) are medications that are traditionally used for depression. While many of these
medications are not FDA indicated specifically for the treatment of diabetes related nerve pain, they
are used by physicians commonly.

The pain of diabetic nerve damage may also improve with better blood sugar control, though
unfortunately blood glucose control and the course of neuropathy do not always go hand in hand.
Newer medications for nerve pain have recently come to market in the US. Pregabalin (Lyrica) which
has an indication for diabetic neuropathic pain and duloxetine (Cymbalta) are newer agents used in
the treatment of diabetic neuropathy.

What can be done to slow diabetes complications?

Findings from the Diabetes Control and Complications Trial (DCCT) and the United Kingdom
Prospective Diabetes Study (UKPDS) have clearly shown that aggressive and intensive control of
elevated levels of blood sugar in patients with type 1 and type 2 diabetes decreases the complications
of nephropathy, neuropathy, retinopathy, and may reduce the occurrence and severity of large blood
vessel diseases. Aggressive control with intensive therapy means achieving fasting glucose levels
between 70-120 mg/dl; glucose levels of less than 160 mg/dl after meals; and a near normal
hemoglobin A1C levels (see below).
Studies in type 1 patients have shown that in intensively treated patients, diabetic eye disease
decreased by 76%, kidney disease decreased by 54%, and nerve disease decreased by 60%. More
recently the EDIC trial has shown that type 1 diabetes is also associated with increased heart disease,
similar to type 2 diabetes. However, the price for aggressive blood sugar control is a two to three fold
increase in the incidence of abnormally low blood sugar levels (caused by the diabetes medications).
For this reason, tight control of diabetes to achieve glucose levels between 70-120 mg/dl is not
recommended for children under 13 years of age, patients with severe recurrent hypoglycemia,
patients unaware of their hypoglycemia, and patients with far advanced diabetes complications. To
achieve optimal glucose control without an undue risk of abnormally lowering blood sugar levels,
patients with type 1 diabetes must monitor their blood glucose at least four times a day and administer
insulin at least three times per day. In patients with type 2 diabetes, aggressive blood sugar control has
similar beneficial effects on the eyes, kidneys, nerves and blood vessels.

Diabetes At A Glance

• Diabetes is a chronic condition associated with abnormally high levels of sugar (glucose) in the
blood.

• Insulin produced by the pancreas lowers blood glucose.

• Absence or insufficient production of insulin causes diabetes.

• The two types of diabetes are referred to as type 1 (insulin dependent) and type 2 (non-insulin
dependent).

• Symptoms of diabetes include increased urine output, thirst and hunger as well as fatigue.

• Diabetes is diagnosed by blood sugar (glucose) testing.

• The major complications of diabetes are both acute and chronic.

o Acutely: dangerously elevated blood sugar, abnormally low blood sugar due to
diabetes medications may occur.

o Chronically: disease of the blood vessels (both small and large) which can damage the
eye, kidneys, nerves, and heart may occur
• Diabetes treatment depends on the type and severity of the diabetes. Type 1 diabetes is treated
with insulin, exercise, and a diabetic diet. Type 2 diabetes is first treated with weight reduction,
a diabetic diet, and exercise. When these measures fail to control the elevated blood sugars,
oral medications are used. If oral medications are still insufficient, insulin medications are
considered.
Diabetes Treatment
Medical Author: Ruchi Mathur, MD
Medical Editor: William C. Shiel, Jr., MD, FACP, FACR and Jay W. Marks, MD

• How is diabetes treated?

• Medications for type 2 diabetes
• Sulfonylureas
• Meglitinides - (Prandin and Starlix)
• Medications that decrease the amount of glucose produced by the liver
• Medications that increase the sensitivity of cells to insulin (Actos and Avandia)
• Medications that decrease the absorption of carbohydrates from the intestine (Precose)
• New medications that effect glycemic control (Symlin and Byetta)
• DPP-IV inhibitors
• Combination medications
• Treatment of diabetes with insulin
• Different methods of delivering insulin
• Pre-filled insulin pens
• Insulin pump
• Inhaled Insulin
• Intranasal, Transderm
• The future of pancreas transplantation
• Related Diabetes Articles:
Diabetes Causes, Symptoms, and Diagnosis - on MedicineNet

1.How is diabetes treated?

The major goal in treating diabetes is to minimize any elevation of blood sugar (glucose) without
causing abnormally low levels of blood sugar. Type 1 diabetes is treated with insulin, exercise, and a
diabetic diet. Type 2 diabetes is treated first with weight reduction, a diabetic diet, and exercise. When
these measures fail to control the elevated blood sugars, oral medications are used. If oral medications
are still insufficient, treatment with insulin is considered.

Adherence to a diabetic diet is an important aspect of controlling elevated blood sugar in patients with
diabetes. The American Diabetes Association (ADA) has provided guidelines for a diabetic diet. The
ADA diet is a balanced, nutritious diet that is low in fat, cholesterol, and simple sugars. The total daily
calories are evenly divided into three meals. In the past two years, the ADA has lifted the absolute ban
on simple sugars. Small amounts of simple sugars are allowed when consumed with a complex meal.
For more, please read the Diabetic Diet article.

Weight reduction and exercise are important treatments for diabetes. Weight reduction and exercise
increase the body's sensitivity to insulin, thus helping to control blood sugar elevations. For more,
please read the Weight Loss and Fitness articles.
2.Medications for type 2 diabetes

WARNING: All the information below applies to patients who are not pregnant or
breastfeeding. At present the only recommended way of controlling diabetes in women who
are pregnant or breastfeeding is by diet, exercise and insulin therapy. You should speak
with your doctor if you are taking these medications and are considering becoming
pregnant or if you have become pregnant while taking these medications.

Based on what is known, medications for type 2 diabetes are designed to:

1. Increase the insulin output by the pancreas.

2. Decrease the amount of glucose released from the liver.

3. Increase the sensitivity (response) of cells to insulin.

4. Decrease the absorption of carbohydrates from the intestine.

5. Slow emptying of the stomach to delay the presentation of carbohydrates for digestion and
absorption in the small intestine.

When selecting therapy for type 2 diabetes, consideration should be given to:

1. The magnitude of change in blood sugar control that each medication will provide.

2. Other coexisting medical conditions (high blood pressure, high cholesterol, etc.)

3. Adverse effects of the therapy

4. Contraindications to therapy

5. Issues that may affect compliance (timing of medication, frequency of dosing)

6. Cost to the patient and the healthcare system

It's important to remember that if a drug can provide more than one benefit (lower blood sugar and
have a beneficial effect on cholesterol, for example), it should be preferred. It's also important to bear
in mind that the cost of drug therapy is relatively small compared to the cost of managing the long-
term complications associated with poorly controlled diabetes.

Varying combinations of medications also are used to correct abnormally elevated levels of blood
glucose in diabetes. As the list of medications continues to expand, treatment options for type 2
diabetes can be better tailored to meet an individuals needs. Not every patient with type 2 diabetes will
benefit from every drug, and not every drug is suitable for each patient. Patients with type 2 diabetes
should work closely with their physicians to achieve an approach that provides the greatest benefits
while minimizing risks.
Patients with diabetes should never forget the importance of diet and exercise. The control of diabetes
starts with a healthy lifestyle regardless of what medications are being used.

Medications that increase the insulin output by the pancreas - sulfonylureas and
meglitinides

Sulfonylureas

Historically, increasing insulin output by the pancreas has been the major area targeted by medications
used to treat type 2 diabetes. Medications that increase the output of insulin belong to a class of drugs
called sulfonylureas. Sulfonylureas primarily lower blood glucose levels by increasing the release of
insulin from the pancreas. Older generations of these drugs include chlorpropamide and tolbutamide,
while newer drugs include glyburide (DiaBeta), glipizide (Glucotrol), and glimepiride (Amaryl).
These drugs are effective in rapidly lowering blood sugar but run the risk of causing hypoglycemia
(abnormally low and dangerous levels of blood sugar). In addition, they are sulfa-containing drugs and
should be avoided by patients who are allergic to sulfa .

Meglitinides - repaglinide (Prandin) and nateglinide (Starlix)

The class of drugs known as meglitinides is relatively new. Meglitinides also work on the pancreas to
promote insulin secretion. Unlike sulfonylureas that bind to receptors on the insulin producing cells,
meglitinides work through a separate potassium based channel on the cell surface. Unlike the
sulfonylureas which last longer in the body, repaglinide (Prandin) and nateglinide (Starlix) are very
short acting, with peak effects within one hour. For this reason, they are given up to three times a day
just before meals. Since these drugs also increase circulating insulin levels, they may cause
hypoglycemia, but the literature suggests this is less frequent than the hypoglycemia seen with
sulfonylureas.

Prandin

In a three month study, repaglinide (Prandin) dropped fasting blood glucose values by 61 mg/dL and
post meal blood glucose values by 100 mg/dL. Because Prandin is short acting and given before
meals, it is particularly beneficial in lowering blood glucose after meals and does not tend to lower
fasting glucose levels to the same degree. Prandin has been used in combination with other
medications, such as metformin (Glucophage), with impressive results. In 83 patients with type 2
diabetes, blood sugar control improved significantly with the addition of Prandin to Glucophage.

Prandin interacts with other medications. Therefore, the doctor must be aware of all other medications
a patient is taking before prescribing Prandin. The usual starting dose is 0.5mg before each meal and
can be increased to 4mg. The maximum daily dose is 16mg. Prandin is used with caution in people
with kidney or liver abnormalities. Since Prandin increases insulin levels, it has the risk of causing
abnormally low blood sugars. Blood sugars that remain severely low can result in sweating, tremors,
confusion, and may lead to coma and seizure. In addition, the use of Prandin has been associated with
headaches, muscle and joint aches, along with sinus infections in some individuals. This drug should
not be used in pregnancy or by nursing mothers. The dose may need to be adjusted in older people,
since the elderly may metabolize (eliminate) medications at a slower rate. For more, please read the
drug information on repaglinide (Prandin).

Starlix

Nateglinide (Starlix) has essentially the same profile of side effects and interactions as Prandin. The
major benefit of Starlix is that the starting dose of 120mg does not need to be adjusted upward, but
rather remains constant. These medications are also relatively safe to use in people with impaired
kidney function. For more, please read the drug information on nateglinide (Starlix).

Medications that decrease the amount of glucose produced by the liver

A class of drugs called biguanides has been used for many years in Europe and Canada. In 1994, the
FDA approved the use of the biguanide metformin (Glucophage) for the treatment of type 2 diabetes
in the U.S. Glucophage is unique in its ability to decrease glucose production by the liver. Briefly,
because metformin does not increase insulin levels, when used alone, it does not usually cause
hypoglycemia. In addition, metformin has an effect whereby it tends to suppress appetite, which may
be beneficial in diabetics who tend to be overweight. Metformin may be used by itself or together with
other oral drugs or insulin. It should not be used in patients with kidney impairment and should be
used with caution in those with liver impairment. The older biguanides that preceded metformin were
associated with a serious condition called lactic acidosis, a dangerous acid build up in the blood
resulting from accumulation of the drug and its breakdown products. While metformin is safer in this
regard, it is recommended that the drug be discontinued for 24 hours before any procedure involving
the intravenous injection of dyes (such as for some x-ray studies of the kidney) or surgery is
performed. The dyes may impair kidney function and cause a build up of the drug in the blood.
Metformin can be restarted after these procedures once the patient is urinating normally.

Medications that increase the sensitivity of cells to insulin

The class of drugs known as thiazolidinediones lowers blood glucose by improving target cell
response to insulin (that is, increasing the sensitivity of the cells to insulin). Troglitazone (Rezulin)
was the first of this class in the U.S. Because of severe toxic liver effects, troglitazone has been taken
off the market. Sister compounds are now available with a better safety profile. These drugs include
pioglitazone (Actos) and rosiglitazone (Avandia).

Pioglitazone (Actos) and rosiglitazone (Avandia) are thiazolidinediones approved for use in the U.S.
While they are sister compounds to Rezulin, extensive studies have failed to show that they are
associated with any liver problems. Both Avandia and Actos act by increasing the sensitivity
(responsiveness) of cells to insulin. They improve the sensitivity of muscle and fat cells to insulin.
These drugs have been effective in lowering blood sugars in patients with type 2 diabetes, Actos and
Avandia act within one hour of administration and are taken once daily. It is important to note that it
takes up to six weeks to see a drop in blood glucose levels with these drugs and up to 12 weeks to see
a maximum benefit. Actos and Avandia have been approved as first line therapy in diabetes and for
use in combination with other drugs. Both drugs may be used in patients taking other oral drugs as
well as those using insulin.
While reported liver problems with these agents are mild (and reversible with discontinuation of the
drug), most physicians choose to follow an earlier recommendation to do blood tests to detect liver
injury every two months or so during the first year of therapy. Recently this recommendation has been
removed. If at any point the liver tests increase to three times the normal upper limit, the drug should
be stopped.

The most important contraindications to these medications include any type of liver disease, and heart
failure. Fluid retention can be of particular concern in patients with signs or symptoms of heart failure
and in those with ejection fractions of less than 40% which indicates poor function of the heart. While
the reports are three to eight pounds, clinical experience shows up to 12–15 pounds of weight gain can
occur. Usually the majority of this is fluid, but an absolute body weight gain can also occur. This is
likely to be dose–dependent and, therefore, the increases in weight may be greater with higher doses of
drug. Weight gain is more pronounced in patients who are also taking insulin. In general, the ankle
swelling and puffiness due to the accumulation of fluid can be controlled with the addition of a
diuretic such as spironolactone (Aldactone) — (furosemide (Lasix) does not work as well) — or by
reducing the dose. On occasion, patients may be symptomatic enough from fluid retention to warrant
withdrawal of the drug. Some recent studies have suggested an association between pioglitazone and
rosiglitazone and untoward cardiac events, for example, heart attacks, though this association is
controversial. Regardless of the controversy, it is well established that pioglitazone and rosiglitazone
should be avoided in patients with symptomatic heart failure or heart failure.

Another newer concern is an association of treatment with a small increase in the frequency of
fractures of the distal long bones of the arms and legs. At present, this does not translate into fractures
of the hip and spine, which would be clinically more worrisome. More data is needed to make a
definitive statement about cause and effect at this time.

As an aside, Actos and Avandia have an added benefit of changing cholesterol patterns in diabetes.
HDL (or good cholesterol) increases with these medications, and triglycerides often decrease. While
there is some controversy regarding what happens to bad cholesterol (LDL) levels, there is a
suggestion that Actos may be superior in changing lipid profiles than Avandia. In this population of
diabetics that is already at an increased risk for heart disease, an improvement in cholesterol profile is
beneficial. As more and more data becomes available, there is mounting evidence that this class of
drugs may provide direct benefits to the heart and large blood vessels and may actually be valuable in
preventing the progression of diabetes in high-risk individuals by reducing inflammation and by
decreasing clotting factors. As time goes on, I have no doubt that the uses for this class of medications
will expand. For more, please read the drug information on pioglitazone (Actos) and rosiglitazone
(Avandia).

Medications that decrease the absorption of carbohydrates from the intestine

Before being absorbed into the bloodstream, carbohydrates must be broken down into smaller sugar
particles, such as glucose, by enzymes in the small intestine. One of the enzymes involved in breaking
down carbohydrates is called alpha glucosidase. By inhibiting this enzyme, carbohydrates are not
broken down as efficiently and glucose absorption is delayed.
Precose

The name of the alpha glucosidase inhibitor available in the U.S. is acarbose (Precose). In clinical
trials with over 700 patients, the use of Precose was associated with a reduction in hemoglobin A1c
values (a well known measurement of average blood sugars over the preceding three months) that was
significantly greater than the use of placebo (no treatment). However, as a single agent, Precose is not
as effective as the other medications for diabetes. Since Precose works in the intestine, its effects are
additive to diabetic medications that work at other sites, such as sulfonylureas. Clinical studies have
shown statistically better control of blood glucose in patients treated with Precose and a sulfonylurea
compared to the sulfonylurea alone. Precose is currently used alone or in combination with a
sulfonylurea.

Precose is taken three times a day at the beginning of meals. The dosage varies from 25 to 100mg with
each meal. The maximum recommended dose is 100mg three times a day. At doses greater than this,
reversible abnormalities in liver tests may be seen. Because of its mechanism of action, Precose has
significant gastrointestinal side effects. Abdominal pain, diarrhea, and gas are common and are seen in
up to 75% of patients taking Precose. For this reason, Precose is administered using a low initial dose
that is increased over weeks depending on the patient's tolerance. Most of the gastrointestinal
symptoms tend to subside over the course of a few weeks although some patients report persistent
problems. For more information, please read the drug information on acarbose (Precose).

New medications that effect glycemic control

Symlin (pramlintide)

Symlin is the first in a new class of injectable, anti-hyperglycemic medications for use in patients with
type 2 or type 1 diabetes treated with insulin. Pramlintide, the active ingredient in Symlin, is a
synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by
pancreatic beta cells that helps control glucose control after meals. Amylin, similar to insulin, is absent
or deficient in patients with diabetes. When used with insulin, this compound can improve glycemic
control and has additional benefits that cannot be realized with insulin alone.

According to published data, Symlin reduces post meal blood sugar peaks, reduces glucose
fluctuations throughout the day, enhances satiety (the sensation of fullness) leading to potential weight
loss, and lowers mealtime insulin requirements. Studies have shown it improves A1C beyond the
effect of insulin alone.

Symlin is taken just prior to meals, three times a day. It is given in injection form and is used for:

• Type 2 diabetes, as an additional treatment in patients who use mealtime insulin therapy and
have failed to achieve desired glucose control despite optimal insulin therapy, with or without a
concurrent sulfonylurea agent and/or metformin.
• Type 1 diabetes, as an additional treatment in patients who use mealtime insulin therapy and
who have failed to achieve desired glucose control despite optimal insulin therapy.
Symlin is considered a therapy option in patients with insulin-using type 2 or type 1 diabetes, that are
unable to achieve adequate glycemic control despite individualized insulin management. Insulin-using
patients with type 2 diabetes may also be taking a concurrent sulfonylurea agent and/or metformin.

The major side effect of Symlin is nausea, and this can be reduced with a slow, steady, increase in
dose. The other major side effect is hypoglycemia (dangerously low levels of blood sugar). To avoid
this, the dose of mealtime insulin should be cut in half when starting Symlin. Of note is the degree of
weight loss seen with Symlin therapy. Studies for up to six months show weight loss of greater than
six pounds more than placebo (inactive pills). For more, please read the drug information on
pramlintide (Symlin).

Byetta (exenatide)

Byetta (exenatide) is a new medication on the market that has it's origins in an interesting place--the
Gila monster's saliva. Scientists studying this small lizard noted it could go a long time without eating.
They found a substance in it's saliva that slowed stomach emptying, thus making the lizard feel fuller
longer. This substance was similar in nature to a gut hormone found in humans known as GLP-1.
GLP-1 is broken down in the body by an enzyme called DPP-IV. So, if you could make a substance
like GLP-1 that was not so easy to breakdown, this would have potential benefit; thus, the studies
began. Ultimately, after modifying this hormone, exenatide (with the trade name Byetta) was
developed. Byetta is the first in a new class of drugs for the treatment of type 2 diabetes called incretin
mimetics. Byetta has been shown to have many of the same effects on sugar regulation as GLP-1, so it
mimics the body's natural physiology for self-regulating blood sugar. Namely, it slows the release of
glucose from the liver, slows stomach emptying thereby regulating delivery of nutrients to the intestine
for absorption, and works centrally in the brain to regulate hunger.

Byetta is indicated as additional therapy to improve control of blood sugars in patients with type 2
diabetes who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea
but who have not achieved adequate sugar control. It enhances the way the insulin producing beta cells
in the pancreas work. Insulin secretion increases only when blood sugars are high and decreases as
blood sugars approach normal. In addition to enhancing the normal physiology of the beta cell, Byetta
suppresses glucose release from the liver, slows stomach emptying and the absorption of nutrients
including carbohydrate, and reduces intake of food.

Just like Symlin, Byetta is given by injection, but it is given twice a day (usually before breakfast and
dinner meals). It comes in a disposable pen form and is available in two doses. The goal is to start with
the lower dose for a month or so and then move up to the higher dose if needed and if tolerated.
Similar to Symlin, the main side effect is nausea, most likely due to its effects on stomach emptying.
This medication is temperature sensitive and it was recommended that the pens be stored at 36-46
degrees F. Recently, this has changed, with a recommendation that unopened pens be refrigerated, and
once opened, the pens can be left at room temperature. The risk of hypoglycemia is still a possibility
with Byetta, especially when used in combination with sulfonylureas. Your physician may choose to
decrease the dose of some of your other medications when initially evaluating how you respond to
Byetta.
Similar to Symlin, weight reduction is seen with Byetta in the majority of patients. This makes it
particularly suitable for the typical patient with type 2 diabetes who is also overweight. For more,
please read the drug information pamphlet on exenatide (Byetta).

A longer acting from of Byetta is currently being considered for approval by the FDA. This would
allow for the same benefits (and side effects) without need for such frequent injections.

DPP-IV inhibitors

GLP-1 in the body is broken down by an enzyme called DPP IV. Logically, you can either make a
synthetic GLP-1 that is not broken down by this enzyme (for example, Byetta) OR you could try to
stop the enzyme that breaks down the GLP-1 your body already makes. Hence, the new class of drugs
called DPP IV inhibitors. They do just that, that is, they inhibit this enzyme from breaking down GLP-
1. This allows GLP-1 already in the blood to circulate longer. There are a number of companies
working on this class of drug and the FDA just approved the first drug in this class made by Merck
and called Januvia. Januvia can be used in combination with certain other medications and must be
dose adjusted in patients with poor kidney function. For more, please read the Januvia pamplet.

These drugs have essentially the same side effect profile as Byetta; however, they are in pill form.
While Byetta has a significant weight loss profile, DPP-IV inhibitors so far have had no effect on
weight.

Combination medications

Glyburide/metformin (Glucovance), rosiglitazone/metformin (Avandamet), glipizide/metformin

(Metaglip), and pioglitazone/metformin (Actosplusmet) are four relatively new combination pills that
are on the market to treat diabetes.

• Glucovance combines glyburide with metformin in varying doses.

• Avandamet is a combination of varying doses of Avandia and metformin.

• Actosplusmet is a combination of varying doses of pioglitazone and metformin.

• Metaglip is a combination pill containing glipizide and metformin in varying strengths.

The benefit to these combination drugs is that there are fewer pills to take, hopefully leading to better
compliance. While they work well, I personally like to give patients individual medications until I
know what doses are working, and then switch to a combination pill once the patient has been stable
on the doses of individual medications for a period of time.

Treatment of diabetes with insulin

Insulin is the mainstay of treatment for patients with type 1 diabetes. Insulin is also important in type 2
diabetes when blood glucose levels cannot be controlled by diet, weight loss, exercise, and oral
medications.
Ideally, insulin should be administered in a manner that mimics the natural pattern of insulin secretion
by a healthy pancreas; however, the complex pattern of insulin secretion by the pancreas is difficult to
duplicate. Still, adequate blood glucose control can be achieved with careful attention to diet, regular
exercise, home blood glucose monitoring, and multiple insulin injections throughout the day. For
more, please see the Diabetes and Home Care Monitoring article.

In the past, the insulin was being derived from animal sources, particularly cows and pigs. Not only
was there a problem with enough supply of insulin to meet the demand, but beef and pork insulin also
had specific problems. Originating from animals, these types of insulin caused immune reactions in
some people. Patients would become intolerant or resistant to animal insulin. With the acceleration of
scientific research in the latter half of the twentieth century, beef and pork insulin were replaced by
human insulin. In 1977, the gene for human insulin was cloned, and through modern technology,
manufactured human insulin was made available. Human insulin is now widely used.

Insulin now comes in a variety of preparations that differ in the amount of time following injection
until they begin to work and the duration of their action. Because of these differences, combinations of
insulin are often used to allow for a more tailored regimen of blood sugar control. The table below lists
the most common types of insulin currently in use in the U.S. and their specific properties.

Name of Insulin Onset of Action Peak Effect After Injection

Humalog and
Novolog//Very Short 5-15 minutes 30-60 minutes
Acting
Regular/Short Acting 30 minutes 2-5 hours
NPH/Intermediate
1-2.5 hours 8-14 hours
Acting
Lente/Intermediate
1-2.5 hours 8-12 hours
Acting
Ultra Lente/Long Acting 4-6 hours 10-18 hours
Lantus 2-3 hours Stable from 2-3 hours to @20 hours
Detemir 3-4 hours Dose dependent (longer acting at higher doses)
Combinations - 75/25,
30 minutes 7-12 hours
70/30, 50/50

For example, a patient may take an injection of Lantus in the morning and evening to provide a
baseline of insulin throughout a 24-hour period. In addition, the same patient may take an injection of
Humalog just before meals to cover the increase in carbohydrate load after eating.

Different methods of delivering insulin

Not only is the variety of insulin preparations growing, so are the methods for administering insulin.

Pre-filled insulin pens

In the past, insulin was available only in an injectable form that involved carrying syringes (which a
few decades ago were made of glass and required sterilization), needles, vials of insulin, and alcohol
swabs. Needless to say, patients often found it difficult to take multiple shots each day, and, as a result,
good blood sugar control was often compromised. Many pharmaceutical companies are now offering
discreet and convenient methods of delivering insulin.

Both Novo Nordisk and Lily have an insulin pen delivery system. This system is similar to an ink
cartridge in a fountain pen. A small pen-sized device holds an insulin cartridge (usually containing 300
units). Cartridges are available in the most widely used insulin formulations, such as those listed in the
table above. The amount of insulin to be injected is dialed in by turning the bottom of the pen until the
required number of units is seen in the dose-viewing window. The tip of the pen consists of a needle
that is replaced with each injection. A release mechanism allows the needle to penetrate just under the
skin and deliver the required amount of insulin. The cartridges and needles are disposed of when
finished and new ones simply are inserted. In many cases, the entire pen is disposed of. These insulin
delivery devices are less cumbersome than traditional methods.

Insulin pump

The most recently available advance in insulin delivery is the insulin pump. In the U. S., MiniMed,
Deltec and Disetronic market the insulin pump. An insulin pump is composed of a pump reservoir
similar to that of an insulin cartridge, a battery-operated pump, and a computer chip that allows the
user to control the exact amount of insulin being delivered. Currently, pumps on the market are about
the size of a pager or beeper. The pump is attached to a thin plastic tube (an infusion set) that has a
cannula (like a needle but soft) at the end through which insulin passes. This cannula is inserted under
the skin, usually on the abdomen. The cannula is changed every two days. The tubing can be
disconnected from the pump while showering or swimming. The pump is used for continuous insulin
delivery, 24 hours a day. The amount of insulin is programmed and is administered at a constant rate
(basal rate). Often, the amount of insulin needed over the course of 24 hours varies depending on
factors like exercise, activity level, and sleep. The insulin pump allows for the user to program many
different basal rates to allow for this variation in lifestyle. In addition, the user can program the pump
to deliver additional insulin during meals to cover the excess demands for insulin caused by the
ingestion of carbohydrates with the meal.

Over 50,000 people worldwide are using an insulin pump. This number is growing dramatically as
these devices become smaller and more user–friendly. Insulin pumps allow for tight blood sugar
control and lifestyle flexibility while minimizing the effects of low blood sugar (hypoglycemia). At
present, the pump is the closest device on the market to an artificial pancreas. More recently, newer
models of the pump have been developed that do not require a tubing, in fact - the insulin delivery
device is placed directly on the skin and any adjustments needed for insulin delivery are made through
a PDA like device that must be kept within a 6 foot range of the insulin delivery device, and can be
worn in a pocket, kept in a purse, or on a tabletop when working.
Probably the most exciting innovation in pump technology is the ability to use the pump in tandem
with newer glucose sensing technology. Glucose sensors have improved dramatically in the last few
years, and are an option for patients to gain further insight into their patterns of glucose response to
tailor a more individual treatment regimen. The newest generation of sensors allows for a real time
glucose value to be given to the patient. The implantable sensor communicates wirelessly with a
pager-sized device that has a screen. The device is kept in proximity to the sensor to allow for transfer
of data, however, it can be a few feet away and still receive transmitted information. Depending on the
model, the screen displays the blood glucose reading, a thread of readings over time, and a potential
rate of change in the glucose values. The sensors can be programmed to produce a "beep" if blood
sugars are in a range that is selected as too high or too low. Some can provide a warning beep if the
drop in blood sugar is occurring too quickly.

To take things one step further, there is one particular sensor that is new to the market that is designed
to communicate directly with the insulin pump. While the pump does not yet respond directly to
information from the sensor, it does "request" a response from the patient if there is a need for
adjustments according to the patterns it is programmed to detect. The ultimate goal of this technology
is to "close the loop" by continuously sensing what the body needs, and then responding by providing
the appropriate dose of insulin. While this technology is a few more years in the making, the strides in
this direction continue to grow.

Inhaled Insulin

Inhaled insulin, marketed by Pfizer in 2006, was approved by the FDA. This inhaled form of insulin is
called Exubera. The insulin is packaged in dry blister packs that are inserted into an inhalation device.
This device lances the powder packs allowing the insulin to enter a chamber that has a mouth piece
through which the user can inhale the insulin. Exubera has a peak of action similar to Humalog (rapid
acting), and a duration of action similar to regular insulin (short acting). It can be combined with oral
medication in patients with type 2 diabetes or used alone. In patients with type 1 diabetes the insulin
should be combined with a longer acting basal insulin such as glargine.

The side effect profile of inhaled insulin is similar to other insulins, and the user must be aware of
hypoglycemia. In addition, since the insulin is absorbed through the lungs, there was initial concern
regarding lung function. While there is a slight decrease in lung function with the initial use of
Exubera, this stabilizes quickly and returns to baseline of aged matched controls when the Exubera is
discontinued. Since this is still a new product, it is recommended that any patient starting on inhaled
insulin have lung function tests done prior to starting treatment. If baseline values of FEV1 (a measure
of lung function) are < 70%, Exubera is not given. After six months of use lung function tests are
performed again; if deterioration is noted, Exubera is discontinued.

Exubera is not to be used in regular or intermittent smokers and patients requiring very small doses of
insulin. Nevertheless, in the right population, this is a great option.

Note: Unfortunately, acceptance of Exubera was poor over the year or so it was available since it's
launch in 2006. Recently in October 2007, the company Pfizer decided not to sell the product
anymore. Part of this issue was the time required to teach the device and the uniqueness of the format
of delivery. While no major medical concerns were noted with it's use, it simply has not been accepted
by patients and doctors. Perhaps we will see this modality come back in a new easier to use
incarnation.

Intranasal, Transdermal

Other routes for the delivery of insulin have also been tried. Intranasal insulin delivery was thought to
be promising. However, this method was associated with poor absorption and nasal irritation.
Transdermal insulin (skin patch delivery) has also yielded disappointing results to date. Insulin in pill
form is also not yet effective since the digestive enzymes in the gut break it down.

The future of pancreas transplantation

Ultimately, the goal in the management of type 1 diabetes is to provide insulin therapy in a manner
that mimics the natural pancreas. Perhaps the closest therapy available at this time is a transplant of the
pancreas. Several approaches to pancreatic transplantation are currently being studied, including the
whole pancreas and isolated islet cells (these groups of cells contain beta cells that are responsible for
insulin production). Data available from 1995 indicates that almost 8,000 patients underwent
pancreatic transplantation. Most patients undergo pancreatic transplantation at the time of kidney
transplantation for diabetic kidney disease.

Transplantation is not without risk. Both the surgery itself and the immunosuppression that must occur
afterward pose significant risks to the patient. For these reasons, the kidney and pancreas are usually
transplanted at the same time. At present, there is disagreement about whole pancreas transplantation
in patients not currently requiring kidney transplantation. The issue of whether the benefits outweigh
the risks in these patients is under debate. There is also a chance that diabetes will occur in the
transplanted pancreas. Selectively transplanting islet cells is an interesting alternative to whole
pancreas transplantation. However, the concern over rejection remains. Attempts to disguise the islet
cells in tissues that the body won't reject (for example, by surrounding the islet cells by the patient's
own cells and then implanting them) are underway. In addition, researchers are exploring artificial
barriers that can surround the islet cells, provide protection against rejection, and still allow insulin to
enter the bloodstream.

A Final Word

These last few years have been an exciting time in diabetes care. Many agents for the treatment of type
2 diabetes are under development and the options for insulin therapy continue to grow and methods for
insulin delivery continue to become more refined. While research continues to expand in these areas,
one thing remains constant. Achieving the best blood sugar control possible remains the ultimate goal
in both type 1 and type 2 diabetes. We now know, beyond a doubt, that good blood sugar control
minimizes the long-term complications of diabetes, including blindness, nerve damage, and kidney
damage. Finally, a healthy lifestyle can do nothing bad...it should remain the cornerstone of
management for diabetes.