Module 15 - Drugs to treat Diabetes

Question 1

Classic symptoms of diabetes

Answer 1

Polyuria (increased urination), polydipsia (increased thirst), polyphagia (increased hunger) and weight loss.

Question 2

Diabetes

Answer 2

Diabetes is a chronic disease characterized by elevated blood levels of glucose (i.e. sugar).

Normally glucose is efficiently reabsorbed in the proximal tubule of the kidney so it is not found in the urine.

In untreated diabetes, blood glucose rises so high that the transporters that reabsorb it are saturated and significant amounts of glucose are found in the urine.

High blood sugar in diabetes results from either not enough insulin produced in the body or because the body’s cells do not respond to the insulin that is produced.

Diabetes occurs when insulin levels are too low or when the body’s cells are resistant to the effects of insulin.

Question 3

what is Insulin

Answer 3

is a hormone produced by the pancreas that is involved in tightly regulating blood glucose.

Question 4

Insulin: the basics

Answer 4

Insulin is a peptide hormone synthesized by the β (beta) cells of the islets of Langerhans of the pancreas.

Insulin is rapidly released from the pancreas into the blood in response to increases in blood glucose.

When insulin is secreted, it causes glucose uptake into muscle, liver, and fat cells.

In liver cells, glucose uptake results in glycogen synthesis (a storage form of glucose).

In muscle cells, glucose is used as energy and promotes protein synthesis.

In fat cells, insulin causes increased synthesis of fatty acids, which results in increased triglyceride synthesis.

Extracellular potassium is important in the action of insulin as it helps insulin to drive glucose into the cell.

Question 5

Types of Diabetes

Answer 5

1. Type I diabetes – Also called insulin dependent diabetes mellitus.
2. Type II diabetes – Also called non-insulin dependent diabetes mellitus.
3. Gestational diabetes – Diabetes that occurs in pregnancy.

Question 6

Type I Diabetes

Answer 6

Approximately 10% of people with diabetes have type I diabetes.

Type I diabetes is usually diagnosed in children or adolescents but symptoms may not appear until early adulthood.

Type I diabetes is caused by an autoimmune reaction where the body’s own immune cells attack and destroy the insulin secreting β cells.

As a result, the body makes too little or no insulin at all and requires insulin replacement.

Type I diabetes is not preventable and it is not caused by eating too much sugar.

Question 7

Type II Diabetes

Answer 7

Approximately 90% of people with diabetes have type II diabetes.

In type II diabetes the pancreas makes sufficient insulin. However, the insulin produced is resistant to use.

Over the course of the disease, insulin synthesis may also decrease.

There are many risk factors for developing type II diabetes including age, having a family member with diabetes, previous gestational diabetes, lack of exercise, heart disease, obesity, ethnicity (African and Native descent are at higher risk).

It is important to note that in Canada, ~ 80% of all patients with type II diabetes are obese or overweight.

Type II diabetes was typically diagnosed later in life but there is a trend towards younger people getting the disease.

Question 8

Gestational Diabetes

Answer 8

Gestational diabetes is diabetes that first starts during pregnancy.

Usually begins ~ halfway through pregnancy.

All women should have an oral glucose tolerance test between weeks 24-28 of pregnancy to test for gestational diabetes.

Usually diet and exercise are sufficient to keep blood glucose levels within normal ranges.

Pregnant women with gestational diabetes tend to have larger babies and babies with hypoglycemia in the first few days of life.

After birth, the mother’s blood sugar usually returns to normal however; blood glucose should be continually monitored as many patients develop diabetes 5 – 10 years later.

Question 9

Diabetic Retinopathy

Answer 9

Diabetic retinopathy is the most common cause of blindness in people under the age of 65.

Hyperglycemia causes damage to retinal capillaries.

Tightly controlling blood sugar minimizes the risk of retinopathy.

Patients with type I or type II diabetes should have an eye exam once a year.

Question 10

Diabetic Nephropathy

Answer 10

Diabetic nephropathy is characterized by proteinuria (protein in the urine), decreased glomerular filtration and increased blood pressure.

Proteinuria is the earliest sign of diabetic nephropathy.

Diabetic nephropathy is the leading cause of morbidity and mortality in patients with type I diabetes.

Tight control of blood glucose both delays and reduces the severity of diabetic nephropathy.

ACE inhibitors and ARBs are useful in preventing diabetic nephropathy. Experts suggest patients with type I diabetes take an ACE inhibitor or ARB regardless of their blood pressure.

Question 11

Cardiovascular Disease (CVD)

Answer 11

CVD including heart attack and stroke are the leading causes of morbidity and mortality in patients with type II diabetics.

Atherosclerosis develops much earlier in patients with diabetes.

CVD in diabetes results from a combination of hyperglycemia and altered lipid metabolism.

Statins reduce cardiovascular events in patients with diabetes, regardless of their LDL cholesterol levels

Question 12

Diabetic Foot Ulcers

Answer 12

Are the most common cause of hospitalization for people with diabetes.

Diabetes accounts for approximately half of all lower limb amputations every year due to infection.

All people with diabetes should have regular foot exams.

Question 13

Diagnosis of Diabetes

Answer 13

Diabetes is diagnosed when plasma glucose levels are elevated.

There are three tests used to diagnose diabetes:
1. Fasting Plasma Glucose Test
2. Casual Plasma Glucose Test
3. Oral Glucose Tolerance Test (OGTT)
4. Glycosylated Hemoglobin

Question 14

Fasting Plasma Glucose Test

Answer 14

Patients fast for at least 8 hours and then have a blood sample drawn to measure blood glucose.

If the fasting plasma glucose is > 7.0 mmol/L then diabetes is diagnosed.

The fasting plasma glucose test is the preferred test for diagnosing diabetes.

Question 15

Casual Plasma Glucose Test

Answer 15

Blood can be drawn at any time no matter what the interval was since the last meal.

For a diagnosis of diabetes, the casual plasma glucose is > 11.1 mmol/L AND the patient displays classic signs of diabetes including polyuria, polydipsia and weight loss.

If an initial casual plasma glucose test suggests diabetes, it is often followed up by a fasting plasma glucose test.

Question 16

Oral Glucose Tolerance Test (OGTT)

Answer 16

This test is used when the other tests are unable to diagnose diabetes definitively.

Patients are given an oral 75 gram dose of glucose and plasma glucose is measured 2 hours later.

If plasma glucose is > 11.1 mmol/L then the patients will be diagnosed with diabetes.

Question 17

Glycosylated Hemoglobin

Answer 17

Upon prolonged exposure in the blood, glucose interacts with hemoglobin to form glycosylated derivatives, mostly HbA1C.

Glycosylated hemoglobin is useful in providing an index of the average blood glucose levels over the previous 2-3 months.

Measuring glycosylated hemoglobin is a good determinant of how well a patient is responding to therapy.

The target for management of diabetes is to maintain HbA1C < 7% of total hemoglobin.

Question 18

Treatment Goals and Lifestyle Modifications

Answer 18

The complications of diabetes arise from prolonged elevations of plasma glucose.

Therefore, the primary goal of diabetes therapy is to maintain tight control of plasma glucose levels.

“Tight control” means keeping plasma glucose levels in the normal range for the entire day.

The targets for plasma glucose are:
o Pre-meal plasma glucose 4.0 - 7.0 mmol/L
o Peak post-meal glucose 5.0 - 10 mmol/L
o HbA1C < 7%

Question 19

Cardiovascular Risk

Answer 19

Blood pressure – systolic < 130, diastolic < 80 (less than)

Lipids – LDL < 2.6 mmol/L, triglycerides < 1.7 mmol/L, HDL (men) > 1.0 mmol/L, HDL (women) > 1.3 mmol/L.

Question 20

Kidney Function

Answer 20

Urine albumin to creatinine ratio < 30 mg/g (albumin/creatinine). (less than)

Question 21

Lifestyle Modifications – Type I Diabetes

Answer 21

Diet
Most patients with type I diabetes are thin, therefore the goal is to maintain weight, not lose it.
- Total caloric intake should be split throughout the day with meals 4-5 hours apart.

Exercise
- Exercise increases the cellular response to insulin and increases glucose tolerance so patients should be encouraged to exercise.
- Strenuous exercise may cause hypoglycemia so close patient oversight is required.

Insulin
- Survival requires insulin.
- Blood glucose levels must be monitored 3 or more times per day.

Question 22

Lifestyle Modifications – Type II Diabetes

Answer 22

Diet is a crucial component of treatment in type II diabetes.

Dietary modifications alone (i.e. caloric restriction) often normalize insulin release and decrease insulin resistance.

Patients with type II diabetes are often obese so losing weight is a treatment goal.

Exercise

Exercise stimulates glucose uptake and should be encouraged in patients with type II diabetes.

Question 23

Metabolic Actions of insulin

Answer 23

Insulin can be thought of as anabolic (i.e. “building up” or conservative).

This means that the actions of insulin promote energy storage and conservation.

Insulin’s anabolic actions include:
- Cellular uptake of glucose into liver, muscle, and fat.
- Glucose uptake results in the formation of glycogen (liver and muscle) and triglycerides (adipose tissue).
- Decreased hepatic gluconeogenesis (i.e. glucose synthesis).
- Cellular uptake of amino acids (mostly into muscle).
- Amino acid uptake results in increased protein synthesis.

Question 24

Insulin Deficiency

Answer 24

Insulin deficiency puts the body into a catabolic (“breaking down”) state.

This means the body favours the breakdown of complex molecules into simpler substances.

The catabolic effects seen in insulin deficiency include:
- Glycogenolysis – conversion of glycogen to glucose.
- Gluconeogenesis – new glucose synthesis.
- Decreased glucose utilization.
- All of these effects contribute to the signs and symptoms of diabetes.
- Notice that these catabolic effects all act to raise blood glucose!

Question 25

Insulin Therapy

Answer 25

There are 7 main types of insulin available to treat diabetes.

The different types of insulin differ in their appearance, time course of action, and route of administration.

The insulins can be separated based on time course of actions:

Short duration-rapid acting
Short duration-slower acting
Intermediate duration
Long duration

Question 26

Short Duration Rapid Acting Insulin

Answer 26

This class includes three different types of insulin:
1. Insulin lispro
2. Insulin aspart
3. Insulin glulisine

This class of insulin is administered in association with meals to control the postprandial (i.e. after eating) rise in glucose.

The route of administration is subcutaneous, although they may be used IV if required.

All three types are supplied as a clear solution.

Question 27

Short Duration Slower Acting Insulin

Answer 27

The only type of short duration slower acting insulin is unmodified human insulin.

Short duration slower acting insulins can be injected before meals to control postprandial rises in glucose or infused to provide basal control of blood glucose.

They can be administered subcutaneously or IM (rare).

Following subcutaneous injection, the insulin molecules form small aggregates (i.e. dimers), which slows absorption.

Supplied as a clear solution

Question 28

Intermediate Duration Insulin

Answer 28

two intermediate-duration insulins:
1. Neutral Protamine Hormone (NPH) insulin
2. Insulin Detemir

The onset of action of both of these are delayed, so they may not be used at mealtime to control postprandial rises in blood glucose.

Instead they are injected once or twice daily to control blood glucose between meals and in the evening.

Why are the actions delayed?

NPH insulin – is insulin conjugated to protamine (a large protein). The protamine makes the molecule less soluble and decreases the absorption.

Insulin Detemir – Insulin detemir molecules bind strongly to each other, which delays absorption.

Both NPH insulin and insulin detemir are administered by subcutaneous injection.

NPH insulin is supplied as a cloudy suspension and insulin detemir is a clear solution.

Question 29

NPH insulin

Answer 29

is insulin conjugated to protamine (a large protein). The protamine makes the molecule less soluble and decreases the absorption.

Question 30

Insulin Detemir

Answer 30

Insulin detemir molecules bind strongly to each other which delays absorption.

Question 31

Long-Acting Insulin

Answer 31

Insulin glargine is the only type of long acting insulin.

The main advantage of insulin glargine is its long duration of action therefore, it is administered by subcutaneous injection once daily at bedtime.

The long duration of action of insulin glargine is attributed to its low solubility at physiological pH. When it’s injected, it forms microprecipitates that slowly dissolve and therefore release insulin glargine in small amounts over an extended time.

Insulin glargine is supplied as a clear solution

Question 32

Mixing Insulins

Answer 32

Sometimes insulin therapy calls for combining a short acting insulin with a longer duration insulin.

It is optimal to be able to mix these insulins into a single syringe to avoid having to take two injections.

Some rules for mixing insulins include:

Only NPH insulin can be mixed with short acting insulins.

When the mixture is prepared, the short acting insulin should be drawn into the syringe first.

Mixtures are stable for 28 days.

Question 33

Complications of Insulin Therapy

Answer 33

The primary complication of insulin treatment is hypoglycemia (blood glucose < 3mmol/L).

Rapid decreases in blood glucose, such as in overdose, result in activation of the sympathetic nervous system which causes:

• Tachycardia
• Palpitations
• Sweating
• Nervousness

When blood glucose levels decrease more gradually, CNS symptoms such as headache, confusion, drowsiness, and fatigue occur.

If hypoglycemia is severe coma, convulsions, or even death may occur.

Question 34

Management of Hypoglycemia

Answer 34

Rapid treatment of hypoglycemia is crucial to prevent irreversible brain damage.

If patients are conscious, fast acting oral sugar should be used. Good examples are glucose tablets, orange juice, corn syrup, honey and pop (not diet).

If the patient is unconscious, IV glucose may be required.

Patients with diabetes are also recommended to keep the hormone glucagon on hand.

Question 35

Glucagon

Answer 35

Glucagon is another hormone produced by the pancreas.

Glucagon causes the conversion of glycogen to glucose (opposite action to insulin), and is therefore effective in treating hypoglycemia.

It is most often used in the community when a hypoglycemic patient is unconscious. Once the patient regains consciousness, oral sugar solutions should be used.

For unconscious patients, IV glucose is preferred to glucagon but is impractical outside of medical supervision.

Glucagon is ineffective in starving or malnourished patients. Why? Malnourished or starving patients often do not have any glycogen stores to begin with.

Question 36

Oral Antidiabetic Drugs

Answer 36

used to treat type II diabetes and are for the most part ineffective in type I diabetes.

There are six classes of oral antidiabetic drugs:

1. Biguanides
2. Sulfonylureas
3. Meglitinides
4. Thiazolidinediones (glitazones)
5. Alpha-glucosidase inhibitors
6. Gliptins

Question 37

Biguanides

Answer 37

Biguanides are often the drug of choice for treating type II diabetes.

Biguanides lower blood glucose in three separate ways:

1. Increases the sensitivity and number of insulin receptors.
2. Decreases hepatic gluconeogenesis.
3. Reduces intestinal glucose absorption.

The major advantage of biguanides is that they don’t increase insulin levels, so they pose no risk of hypoglycemia.

Question 38

Adverse effects of Biguanides

Answer 38

Nausea
Decreased appetite
Diarrhea
Decreased absorption of vitamin B12 and folic acid.
Lactic acidosis is rare but serious (mortality in ~ 50% of patients that get it).

Question 39

Sulfonylureas

Answer 39

Act primarily by stimulating release of insulin from the pancreas.

They also inhibit glycogenolysis (the breakdown of glycogen to glucose).

There are “1st generation” and “2nd generation” sulfonylureas.

The major difference between the two generations is that second generation sulfonylureas are much more potent and cause fewer drug interactions.

The major adverse effect of sulfonylureas is hypoglycemia.

Prolonged use may cause pancreatic burnout (i.e. the pancreas has a reduced capacity to synthesize insulin).

Question 40

Adverse effects of sulfonylureas

Answer 40

Hypoglycemia

Question 41

Meglitinides

Answer 41

Meglitinides have the same mechanism of action as sulfonylureas, as they stimulate insulin release from the pancreas.

Meglitinides differ from sulfonylureas in that they:

• Have a short half life so they are effective for treating postprandial rises in glucose.
• Less likely to cause hypoglycemia.
• Less likely to cause pancreatic burnout.

Question 42

Thiazolidinediones (Glitazones)

Answer 42

Glitazones act by increasing insulin sensitivity in target tissues and decreasing hepatic gluconeogenesis.

Glitazones activate the PPARγ (gamma) receptor, which is an intracellular receptor.

Activation of PPARγ turns on genes that regulate carbohydrate metabolism.

The result is increased sensitivity to insulin by increases in the number of glucose transporters.

Glitazones also increase HDL and decrease triglyceride levels via activation of PPARα

Question 43

The adverse effects of glitazones

Answer 43

Fluid retention/edema
Headache
Myalgia

Question 44

Alpha-Glucosidase Inhibitors

Answer 44

Act at the intestine to delay carbohydrate absorption.

In order to be absorbed, the complex carbohydrates in our diet must be broken down into monosaccharides (single sugar molecules). This process is mediated by alpha-glucosidase, an enzyme in the intestine.

Alpha-glucosidase inhibitors block the enzyme and therefore cause a decrease in complex carbohydrate metabolism. This reduces the postprandial rise in glucose.

Adverse effects are limited to the intestine since alpha-glucosidase inhibitors are poorly absorbed.

Question 45

Adverse effects of Alpha-Glucosidase Inhibitors

Answer 45

Flatulence
Cramps
Abdominal distention
Diarrhea
Decreased iron absorption

Adverse effects are limited to the intestine since alpha-glucosidase inhibitors are poorly absorbed.

Question 46

Gliptins

Answer 46

Gliptins act to inhibit an enzyme called dipeptidyl peptidase 4 (DPP-4).

DPP-4 breaks down the incretin hormones GLP-1 and GIP.

Incretin hormones, such as GLP-1 and GIP, are released from the GI tract after a meal. GLP-1 and GIP cause:

1. Increased release of insulin
2. Decreased release of glucagon

By inhibiting DPP-4, gliptins allow more GLP-1 and GIP to reach the pancreas therefore causing increased insulin release and suppression of glucagon release.

Gliptins have no known major adverse effects.

Question 47

Incretin Mimetics

Answer 47

Incretin mimetics are synthetic incretin analogs that mimic the actions of incretin hormones.

Therefore incretin mimetics cause an increase in insulin release and a decrease in glucagon release.

Incretin mimetics are administered by subcutaneous injection and are used as adjunctive therapy with biguanides or sulfonylureas.