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Diabetes mellitus("sweet urine")
Diabetes mellitus is actually not one disease, but a group of disorders in which glucose levels are
elevated in the blood. It is called a protean (widespread) disease because it affects every system in the
body. By itself, it ranks somewhere between fourth and sixth as a leading cause of death in the US -- and
climbing the charts throughout the rest of the world. But when considered as a major factor in
cardiovascular disease and kidney failure, its true impact is probably much higher. Its name, sweet urine,
comes from the fact that it was originally diagnosed by tasting (not testing) the patient's urine. The word
"mellitus" is Latin for honey-sweet. Elevated glucose levels make the urine sweet. Back then, doctors truly
earned their fees.
Doctors often refer to the clinical manifestations of diabetes as the "three polys":
 Polyuria: copious amounts of urine.
 Polydipsia: excessive thirst and drinking of water -- caused by the polyuria.

2.  Polyphagia: excessive eating. Patients with diabetes are actually starving because they're not getting
sugar into their cells where it is needed -- so they are driven to eat excessively, in an attempt to
compensate.
There are two main types of diabetes. Type I is insulin-dependent diabetes mellitus and Type II is non-
insulin-dependent diabetes, formerly known as maturity-onset or adult onset diabetes. There is also a
third, less common, type of diabetes that results from mutant genes inherited from one or both parents.
We will discuss all three types.
Type II diabetes
At one time, Type II diabetes was known as adult onset diabetes because almost all its victims tended to
be over 40 years of age. But those days are long gone, and now, thanks to catastrophic dietary changes
in the developed world (and with developing countries struggling to imitate us) Type II diabetes is now
appearing in many children. So it has been renamed. It is now called non-insulin-dependent diabetes and
accounts for some 90% of all diabetes cases. In fact, children now account for 20% of all newly-
diagnosed cases of Type II diabetes and, like their adult counterparts, are usually overweight. Sadly, it is
almost always a self-inflicted disease -- most often triggered by high glycemic diets and excessive weight.
Fortunately, because it is self-inflicted, it is usually much milder than Type I diabetes (at least if caught in
the early stages) and is much easier to control. In fact, many patients have normal insulin levels. The
problem is that because the body has had to pump out so much insulin over time to combat the high
glycemic foods dominating so many diets, the cells of the body have become progressively less sensitive
to the action of insulin. They have, to use the common term, become insulin resistant.
Although virtually every single cell in the body survives by converting glucose to energy, skeletal muscle
is the major "sink" for removing excess glucose from the blood and converting it into glycogen). But in a
Type II diabetic, the ability of skeletal muscle to remove glucose from the blood and convert it into
glycogen may be only 20% of normal. This, again, is called insulin resistance. Fortunately, vigorous
exercise increases the ability of skeletal muscle to transport glucose across its cellular membrane, thus
reducing the effect of insulin resistance. Or to put it another way, people who lead sedentary lives are
more likely to develop Type II diabetes.
Symptoms of Type II diabetes are similar to that found in Type I and include the three polys mentioned
above.
Treatment options include:
 For most patients -- diet, weight loss, and exercise.
 For some patients -- pharmaceutical drugs.
 For a few patients -- insulin injections.
On the other hand, if patients are lax and do not control their disease early on, symptoms become more
severe over time. It is as though after years of pumping out insulin in an effort to overcome the patient's
insulin resistance, the beta cells become exhausted.

3. The Endocrine System: The Pancreas & Diabetes
The pancreas functions in two modes.
The pancreas functions in two distinctly different modes. It is both an exocrine digestive organ that
secretes digestive juices and enzymes into the duct of Wirsung that runs down the middle of the pancreas
and empties into the duodenum at the head of the pancreas. But the pancreas is also
an endocrine organ, producing insulin, glucagon, and somatostatin that flow directly into the bloodstream,
eventually reaching virtually every cell in the body.
Anatomy review
Physically, the pancreas is located in the upper abdominal cavity, towards the back -- in the C curve of
the duodenum. It is about 12 inches long and tapers from right to left. The thick part, the head, comprises
almost 50% of the mass of the pancreas and lies to the right, nestled in the C-curve of the duodenum. As
for the body of the pancreas, it moves up and to the left, tapering into what is known as the tail of the
pancreas, which terminates at the junction of the spleen.
As might be suspected for such an important organ, the pancreas is richly supplied with arteries and
veins. It is served by branches from the hepatic artery, the gastroduodenal artery, the
pancreaticoduodenal artery, the superior mesenteric artery, and the splenic artery.
Ninety-nine percent of the pancreas is made of acini, clusters of cells that resemble a many-lobed "berry"
(acinus is Latin for berry). The acini produce exocrine digestive juices that flow out of the acini through
small ducts that eventually join together and feed into the duodenum through the pancreatic duct. But
today, we are not interested in that ninety-nine percent. We are interested in the one percent of the
pancreas that is made up of several million cells scattered throughout the pancreas, grouped together in
globules known as islets of Langerhans. It is these cells that contain the endocrine functioning of the
pancreas. A healthy human pancreas contains about one million such globules, which are distributed
throughout the organ like tiny islets in a vast ocean of acini -- hence their name. Their combined mass is
a mere 1 to 1.5 grams.
Physiology of the endocrine pancreas -- four cell types
A single islet of Langerhans is actually comprised of four distinct types of cells (alpha, beta, delta, and
gamma), two of which are primary: alpha and beta.
Alpha cells
Alpha cells constitute 20% of the islet's cells. They secrete the hormone glucagon, a polypeptide of 29
amino acids, which raises blood sugar to maintain normal levels. For the most part, glucagon does not
present the same problems as insulin and will not raise blood sugar much above normal -- 80-100 mg of
sugar per 100 ccs of blood. For obvious reasons (diabetes), we don't want blood sugar to go too high. But

4. for the brain, we don't want it to go too low either (hypoglycemia). The brain does not store sugar and has
no reserves. If blood sugar falls too low, the brain is affected in minutes, possibly even seconds. Note: all
of the islet cells are serviced by an abundant network of capillaries that carry their "products," including
glucagon, out into the bloodstream.
The production and release of glucagon in the pancreas is regulated by chemoreceptors throughout the
body that constantly measure the amount of sugar in the blood. Whenever blood sugar gets too low, the
chemoreceptors signal the alpha cells in the pancreas to release more glucagon. Glucagon in turn travels
through the bloodstream to the liver, where it acts on hepatocytes (cells in the liver) to break
down glycogen (the stored form of glucose) into glucose through a process called glycogenolysis. Also, if
required, the body can convert amino acids and/or fat into intermediate metabolites that are ultimately
converted into glucose through a process called gluconeogenesis. In either case, the glucose makes its
way into the bloodstream where it is available to be used by cells for energy.
Correspondingly, higher-than-normal blood sugar turns off the release of glucagon.
It should also be noted that stimulation of the sympathetic nervous system in preparation for stress, or
flight (or in response to fright) also affects glucagon release; it increases it. This is accomplished through
both neural and hormonal signals coming down into the pancreas. Hormonally, we're talking about
epinephrine and norepinephrine, which stimulate the release of glucagon, thus raising blood sugar levels.
And finally, glucagon secretion is inhibited by amylin, a peptide of 37 amino acids, which is secreted by
the beta cells of the pancreas.
Injections of glucagon are sometimes given to diabetics suffering from an insulin reaction in order to
speed the return of normal levels of blood sugar. All of glucagon's actions tend to counter those of insulin,
which works to reduce the level of glucose in the blood. Incidentally, glucagon, like insulin, is readily
available thanks to genetically engineered bacteria and recombinant DNA technology. This is done by
inserting the human gene for insulin into E. coli bacteria, which then "grow" genuine, bio-identical, human
insulin in culture tanks. For those squeamish about E. coli, this process is also done by some
manufacturers using yeast instead of bacteria.
Beta cells
Beta cells constitute approximately 80% of islet cells. They secrete insulin, which lowers blood sugar --
also in response to chemoreceptors. Higher-than-normal blood sugar stimulates beta cells to release
insulin. Sustained high blood sugar is bad not only for the blood but also for organs and cells.
Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete
insulin in response to a rising level of circulating glucose (i.e. "blood sugar").
Insulin
Insulin is a small protein that affects virtually every single cell in the body and most organs -- primarily by
regulating how every cell in the body utilizes glucose. Seventy-five percent of that glucose is ultimately
used by the body to sustain brain function. The remaining 25% is divided between muscle function, red
blood cell production, and powering every single cell in the body. Actually, glucose does not power those

5. cells directly, but rather, through a process known asglycolysis, it is used in the creation of pyruvate,
which is then turned into adenosine triphosphate (ATP), the actual energy source within the cell.
Again, insulin is a primary regulator of sugar in the body. For example, it stimulates skeletal muscle fibers
to take up glucose and convert it into glycogen, which is the storage form of glucose and is utilized in
muscle tissue to produce ATP by the muscle itself. Insulin also works inside muscle tissue to extract
amino acids from the blood and stimulate theirconversion into protein, thereby causing the muscles to
"grow."
Insulin also acts on liver cells, stimulating them to take up glucose from the blood and convert it into
glycogen while inhibiting production of the enzymes involved in breaking glycogen back down into
glucose and inhibiting the conversion of fats and proteins into glucose. In this way, insulin helps regulate
the body's energy storage system. It should be noted that when the dietary intake of high glycaemic
carbohydrates is excessive, this leads to an excess of stored fat in the liver, which ultimately
compromises liver function. This is further compounded by the fact that insulin acts on fat cells to
stimulate their uptake of glucose and the synthesis of fat.
In each case, insulin triggers these effects by binding to the insulin receptor -- a trans membrane protein
embedded in the plasma membrane of the responding cells.
Taken together, all of these insulin actions result in the storage of the soluble nutrients absorbed from the
intestine into insoluble, energy-rich products (glycogen, protein, fat) and a drop in the level of blood sugar.
Specifically, insulin is glucagon's opposite and acts on the cells of the body to:
 Increase the speed and ability of glucose to diffuse into cells -- especially the skeletal muscles and
heart muscles for the restoration and recovery of those muscles.
 Accelerate the conversion of glucose into its storage form, glycogen.
 Increase the synthesis of proteins from amino acids.
 Increase the synthesis of fatty acids -- especially in the liver. This is the mechanism animals in the
wild use to store energy for hibernation or just to survive harsh winters. Unfortunately, it causes
problems for modern man as we no longer face such extreme conditions -- thus leading to an excess
of fat storage.
 It decreases the rate of glycogenolysis (breakdown of glycogen into glucose) and gluconeogenesis
(conversion of fats and proteins into glucose). The net effect is to lower glucose levels.
Lower-than-normal blood glucose turns off the output of insulin. But there are other factors that also affect
insulin release. The parasympathetic nervous system can stimulate insulin release to aid in recovery and
rest. Glucagon itself causes insulin release to balance its effect in a negative feedback loop. And
finally, gastric inhibitory peptide (GIP) from the enteroendocrine cells of the small intestine responds to
glucose in the lumen of the gut, thereby signalling the "preparatory" release of glucose-dependent insulin
from pancreatic beta cells. It should be noted that the effect of GIP on the pancreas is diminished by Type
2 diabetes.

6. And finally, beta cells also produce insulin-like growth factors (specifically, IGF-2), which is found in many
body tissues at concentrations far higher than insulin itself. It shares the molecular structure and shape of
insulin and is involved in growth. As a side note, IGF-1 (produced in the liver) and IGF-2 are used by
cancer cells to stimulate growth.
Delta cells
Delta cells constitute less than 1% of pancreatic islets. They secrete somatostatin, the same growth-
hormone-inhibiting hormone secreted by the hypothalamus. This hormone inhibits insulin release and
slows absorption of nutrients from the GI tract.
Gamma cells (F cells)
Gamma cells also constitute less than 1% of pancreatic islets. They secrete a pancreatic polypeptide that
inhibits the release of somatostatin. In other words, Delta cells and Gamma cells work to regulate each
other.
Tests and diagnosis
To diagnose type 2 diabetes, you'll be given a:
 Glycatedhemoglobin (A1C) test. This blood test indicates your average blood sugar level for the
past two to three months. It measures the percentage of blood sugar attached to hemoglobin, the
oxygen-carrying protein in red blood cells. The higher your blood sugar levels, the more hemoglobin
you'll have with sugar attached. An A1C level of 6.5 percent or higher on two separate tests indicates
you have diabetes. A result between 5.7 and 6.4 percent is considered prediabetes, which indicates a
high risk of developing diabetes. Normal levels are below 5.7 percent.
If the A1C test isn't available, or if you have certain conditions — such as if you're pregnant or have an
uncommon form of hemoglobin (known as a hemoglobin variant) — that can make the A1C test
inaccurate, your doctor may use the following tests to diagnose diabetes:
 Random blood sugar test. A blood sample will be taken at a random time. Blood sugar values are
expressed in milligrams per deciliter (mg/dL) or millimoles per liter (mmol/L). Regardless of when you
last ate, a random blood sugar level of 200 mg/dL (11.1 mmol/L) or higher suggests diabetes,

7. especially when coupled with any of the signs and symptoms of diabetes, such as frequent urination
and extreme thirst.
 Fasting blood sugar test. A blood sample will be taken after an overnight fast. A fasting blood sugar
level less than 100 mg/dL (5.6 mmol/L) is normal. A fasting blood sugar level from 100 to 125 mg/dL
(5.6 to 6.9 mmol/L) is considered prediabetes. If it's 126 mg/dL (7 mmol/L) or higher on two separate
tests, you have diabetes.
 Oral glucose tolerance test. For this test, you fast overnight, and the fasting blood sugar level is
measured. Then you drink a sugary liquid, and blood sugar levels are tested periodically for the next
two hours.
A blood sugar level less than 140 mg/dL (7.8 mmol/L) is normal. A reading of more than 200 mg/dL
(11.1 mmol/L) after two hours indicates diabetes. A reading between 140 and 199 mg/dL (7.8 mmol/L
and 11.0 mmol/L) indicates prediabetes.
The American Diabetes Association recommends routine screening for type 2 diabetes beginning at age
45, especially if you're overweight. If the results are normal, repeat the test every three years. If the
results are borderline, ask your doctor when to come back for another test.
Screening is also recommended for people who are under 45 and overweight if there are other heart
disease or diabetes risk factors present, such as a sedentary lifestyle, a family history of type 2 diabetes,
a personal history of gestational diabetes or blood pressure above 140/90 millimeters of mercury (mm
Hg).
If you're diagnosed with diabetes, the doctor may do other tests to distinguish between type 1 and type 2
diabetes — since the two conditions often require different treatments.
Treatments and drugs
Management of type 2 diabetes includes:
 Healthy eating
 Regular exercise
 Possibly, diabetes medication or insulin therapy
 Blood sugar monitoring
These steps will help keep your blood sugar level closer to normal, which can delay or prevent
complications.
Healthy eating

8. Contrary to popular perception, there's no specific diabetes diet. However, it's important to center your
diet on these high-fiber, low-fat foods:
 Fruits
 Vegetables
 Whole grains
You'll also need to eat fewer animal products, refined carbohydrates and sweets.
Low glycemic index foods also may be helpful. The glycemic index is a measure of how quickly a food
causes a rise in your blood sugar. Foods with a high glycemic index raise your blood sugar quickly. Low
glycemic foods may help you achieve a more stable blood sugar. Foods with a low glycemic index
typically are foods that are higher in fiber.
A registered dietitian can help you put together a meal plan that fits your health goals, food preferences
and lifestyle. He or she can also teach you how to monitor your carbohydrate intake and let you know
about how many carbohydrates you need to eat with your meals and snacks to keep your blood sugar
levels more stable.
Physical activity
Everyone needs regular aerobic exercise, and people who have type 2 diabetes are no exception. Get
your doctor's OK before you start an exercise program. Then choose activities you enjoy, such as
walking, swimming and biking. What's most important is making physical activity part of your daily routine.
Aim for at least 30 minutes of aerobic exercise most days of the week. Stretching and strength training
exercises are important, too. If you haven't been active for a while, start slowly and build up gradually.
A combination of exercises — aerobic exercises, such as walking or dancing on most days, combined
with resistance training, such as weightlifting or yoga twice a week — often helps control blood sugar
more effectively than either type of exercise alone.
Remember that physical activity lowers blood sugar. Check your blood sugar level before any activity.
You might need to eat a snack before exercising to help prevent low blood sugar if you take diabetes
medications that lower your blood sugar.
Monitoring your blood sugar
Depending on your treatment plan, you may check and record your blood sugar level every now and then
or, if you're on insulin, multiple times a day. Ask your doctor how often he or she wants you to check your
blood sugar. Careful monitoring is the only way to make sure that your blood sugar level remains within
your target range.

9. Sometimes, blood sugar levels can be unpredictable. With help from your diabetes treatment team, you'll
learn how your blood sugar level changes in response to food, exercise, alcohol, illness and medication.
Diabetes medications and insulin therapy
Some people who have type 2 diabetes can achieve their target blood sugar levels with diet and exercise
alone, but many also need diabetes medications or insulin therapy. The decision about which medications
are best depends on many factors, including your blood sugar level and any other health problems you
have. Your doctor might even combine drugs from different classes to help you control your blood sugar
in several different ways.
Examples of possible treatments for type 2 diabetes include:
 Metformin (Glucophage, Glumetza, others). Generally, metformin is the first medication prescribed
for type 2 diabetes. It works by improving the sensitivity of your body tissues to insulin so that your
body uses insulin more effectively.
Metformin also lowers glucose production in the liver. Metformin usually won't lower blood sugar
enough on its own. Your doctor will also recommend lifestyle changes, such as losing weight and
becoming more active.
Nausea and diarrhea are possible side effects of metformin. These side effects usually go away as
your body gets used to the medicine. If metformin and lifestyles changes aren't enough to control your
blood sugar level, other oral or injected medications can be added.
 Sulfonylureas. These medications help your body secrete more insulin. Examples of medications in
this class include glyburide (DiaBeta, Glynase), glipizide (Glucotrol) and glimepiride (Amaryl).
Possible side effects include low blood sugar and weight gain.
 Meglitinides. These medications work like sulfonylureas by encouraging the body to secrete more
insulin, but they're faster acting, and they don't stay active in the body for as long. They also have a
risk of causing low blood sugar, but not as much risk as sulfonylureas do.
Weight gain is a possibility with this class of medications as well. Examples include repaglinide
(Prandin) and nateglinide (Starlix).
 Thiazolidinediones. Like metformin, these medications make the body's tissues more sensitive to
insulin. This class of medications has been linked to weight gain and other more serious side effects,
such as an increased risk of heart failure and fractures. Because of these risks, these medications
generally aren't a first-choice treatment.
Rosiglitazone (Avandia) and pioglitazone (Actos) are examples of thiazolidinediones.

10.  DPP-4 inhibitors. These medications help reduce blood sugar levels, but tend to have a modest
effect. They don't seem to cause weight gain. Examples of these medications are sitagliptin (Januvia),
saxagliptin (Onglyza) and linagliptin (Tradjenta).
 GLP-1 receptor agonists. These medications slow digestion and help lower blood sugar levels,
though not as much as sulfonylureas. This class of medications isn't recommended for use alone.
Exenatide (Byetta) and liraglutide (Victoza) are examples of GLP-1 receptor agonists. Possible side
effects include nausea and an increased risk of pancreatitis.
 SGLT2 inhibitors. These are the newest diabetes drugs on the market. They work by preventing the
kidneys from reabsorbing sugar in the blood. Instead, the sugar is excreted in the urine.
Examples include canagliflozin (Invokana) and dapagliflozin (Farxiga). Side effects may include yeast
infections and urinary tract infections.
 Insulin therapy. Some people who have type 2 diabetes need insulin therapy as well. In the past,
insulin therapy was used as last resort, but today it's often prescribed sooner because of its benefits.
Because normal digestion interferes with insulin taken by mouth, insulin must be injected. Depending
on your needs, your doctor may prescribe a mixture of insulin types to use throughout the day and
night. Often, people with type 2 diabetes start insulin use with one long-acting shot at night.
Insulin injections involve using a fine needle and syringe or an insulin pen injector — a device that
looks similar to an ink pen, except the cartridge is filled with insulin.
There are many types of insulin, and they each work in a different way. Options include:
o Insulin glulisine (Apidra)
o Insulin lispro (Humalog)
o Insulin aspart (Novolog)
o Insulin glargine (Lantus)
o Insulin detemir (Levemir)
o Insulin isophane (Humulin N, Novolin N)
Discuss the pros and cons of different drugs with your doctor. Together you can decide which medication
is best for you after considering many factors, including costs and other aspects of your health.
In addition to diabetes medications, your doctor might prescribe low-dose aspirin therapy as well as blood
pressure and cholesterol-lowering medications to help prevent heart and blood vessel disease.
Bariatric surgery

11. If you have type 2 diabetes and your body mass index (BMI) is greater than 35, you may be a candidate
for weight-loss surgery (bariatric surgery). Blood sugar levels return to normal in 55 to 95 percent of
people with diabetes, depending on the procedure performed. Surgeries that bypass a portion of the
small intestine have more of an effect on blood sugar levels than do other weight-loss surgeries.
Drawbacks to the surgery include cost, and there are risks involved, including a risk of death. Additionally,
drastic lifestyle changes are required and long-term complications may include nutritional deficiencies and
osteoporosis.
Pregnancy
Women with type 2 diabetes may need to alter their treatment during pregnancy. Many women use
insulin therapy during pregnancy. Cholesterol-lowering medications and some blood pressure drugs can't
be used during pregnancy.
If you have signs of diabetic retinopathy, it may worsen during pregnancy. Visit your ophthalmologist
during the first trimester of your pregnancy and at one year postpartum.
Signs of trouble
Because so many factors can affect your blood sugar, problems sometimes arise that require immediate
care, such as:
 High blood sugar (hyperglycemia). Your blood sugar level can rise for many reasons, including
eating too much, being sick or not taking enough glucose-lowering medication. Check your blood
sugar level often, and watch for signs and symptoms of high blood sugar — frequent urination,
increased thirst, dry mouth, blurred vision, fatigue and nausea. If you have hyperglycemia, you'll need
to adjust your meal plan, medications or both.
 Hyperglycemic hyperosmolar nonketotic syndrome (HHNS). Signs and symptoms of this life-
threatening condition include a blood sugar reading higher than 600 mg/dL (33.3 mmol/L), dry mouth,
extreme thirst, fever greater than 101 F (38 C), drowsiness, confusion, vision loss, hallucinations and
dark urine. Your blood sugar monitor may not be able to give you an exact reading at such high levels
and may instead just read "high."
HHNS is caused by sky-high blood sugar that turns blood thick and syrupy. It tends to be more
common in older people with type 2 diabetes, and it's often preceded by an illness or infection. HHNS

12. usually develops over days or weeks. Call your doctor or seek immediate medical care if you have
signs or symptoms of this condition.
 Increased ketones in your urine (diabetic ketoacidosis). If your cells are starved for energy, your
body may begin to break down fat. This produces toxic acids known as ketones.
Watch for loss of appetite, weakness, vomiting, fever, stomach pain and fruity-smelling breath. You
can check your urine for excess ketones with an over-the-counter ketones test kit. If you have excess
ketones in your urine, consult your doctor right away or seek emergency care. This condition is more
common in people with type 1 diabetes but can sometimes occur in people with type 2 diabetes.
 Low blood sugar (hypoglycemia). If your blood sugar level drops below your target range, it's
known as low blood sugar (hypoglycemia). Your blood sugar level can drop for many reasons,
including skipping a meal or getting more physical activity than normal. Low blood sugar is most likely
if you take glucose-lowering medications that promote the secretion of insulin or if you're taking
insulin.
Check your blood sugar level regularly, and watch for signs and symptoms of low blood sugar —
sweating, shakiness, weakness, hunger, dizziness, headache, blurred vision, heart palpitations,
slurred speech, drowsiness, confusion and seizures.
If you develop hypoglycemia during the night, you might wake with sweat-soaked pajamas or a
headache. Due to a natural rebound effect, nighttimehypoglycemia might cause an unusually high
blood sugar reading first thing in the morning.
If you have signs or symptoms of low blood sugar, drink or eat something that will quickly raise your
blood sugar level — fruit juice, glucose tablets, hard candy, regular (not diet) soda or another source
of sugar. Retest in 15 minutes to be sure your blood glucose levels are normal.
If they're not, treat again and retest in another 15 minutes. If you lose consciousness, a family
member or close contact may need to give you an emergency injection of a hormone that stimulates
the release of sugar into the blood (glucagon).