Module 15 Flashcards
1
Q
What is diabetes?
A
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.
2
Q
Many years ago, how was diabetes diagnosed?
A
By the sweet smell and taste of the urine.
3
Q
High blood sugar in diabetes results from what?
A
Either not enough insulin produced in the body or because the body’s cells do not respond to the insulin that is produced.
(therefore there are primarily two main types of diabetes)
4
Q
What are the classic symptoms of diabetes?
A
- polyuria (increased urination)
- polydipsia (increased thirst)
- polyphagia (increased hunger)
- weight loss
5
Q
What is insulin?
A
Insulin is a hormone produced by the pancreas that is involved in tightly regulating blood glucose.
- Diabetes occurs when insulin levels are too low or when the body’s cells are resistant to the effects of insulin.
6
Q
What are the three distinct groups that diabetes can be classified into?
A
- Type I diabetes – Also called insulin dependent diabetes mellitus.
- Type II diabetes – Also called non-insulin dependent diabetes mellitus.
- Gestational diabetes – Diabetes that occurs in pregnancy.
7
Q
Insulin is a _____ hormone synthesized by the _____ cells of the _____ of the pancreas.
A
peptide, β (beta), islets of Langerhans
8
Q
Insulin is rapidly released from the pancreas into the blood in response to what?
A
increases in blood glucose
9
Q
When insulin is secreted, it causes glucose uptake into where?
A
muscle, liver, and fat cells
10
Q
In liver cells, glucose uptake results in what?
A
glycogen synthesis (a storage form of glucose)
11
Q
In muscle cells, glucose is used as energy and promotes what?
A
protein synthesis
12
Q
In fat cells, insulin causes increased synthesis of fatty acids, which results in what?
A
increased triglyceride synthesis
13
Q
Extracellular potassium is important in the action of insulin as it helps insulin to do what?
A
drive glucose into the cell
14
Q
Approximately how many people with diabetes have type 1 diabetes?
A
10%
15
Q
Type 1 diabetes is usually diagnosed when?
A
In children (aged 4-7) or adolescents (aged 10-14); however, symptoms may not appear until early adulthood.
16
Q
What is type 1 diabetes believed to be caused by?
A
It is believed to be 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.
17
Q
Is type 1 diabetes preventable?
A
No, and therefore it is not caused by eating too much sugar
18
Q
Approximately how many people with diabetes have type 2 diabetes?
A
90%
19
Q
In type II diabetes the pancreas makes sufficient insulin, however, the insulin produced is what?
A
The insulin produced is resistant to use.
- Over the course of the disease, insulin synthesis may also decrease.
20
Q
What are some of the many risk factors for developing type 2 diabetes?
A
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)
21
Q
In Canada, what percentage of all patients with type II diabetes are obese or overweight?
A
~ 80%
22
Q
When is type 2 diabetes typically diagnosed?
A
It is typically diagnosed later in life but there is a trend towards younger people getting the disease.
23
Q
What is gestational diabetes?
A
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 blood sugar of the mother usually returns to normal however; blood glucose should be continually monitored as many patients develop diabetes 5 – 10 years later.
24
Q
What is diabetic retinopathy?
A
- 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.
25
Define hyperglycemia
an excess of glucose in the bloodstream, often associated with diabetes mellitus
26
Define hypoglycemia
Low blood glucose, also called low blood sugar or hypoglycemia, occurs when the level of glucose in your blood drops below what is healthy for you.
27
Describe 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.
28
What is diabetic nephropathy characterized by?
proteinuria (protein in the urine), decreased glomerular filtration and increased blood pressure
29
What is the earliest sign of diabetic nephronpathy?
proteinuria
30
What are the leading causes of morbidity and mortality in patients with type 2 diabetes?
CVD including heart attack and stroke
31
What develops much earlier in patients with diabetes?
Atherosclerosis
32
CVD in diabetes results from what?
A combination of hyperglycemia and altered lipid metabolism.
33
What reduce cardiovascular events in patietns with diabetes, regardless of their LDL cholesterol levels?
Statins
34
What is the most common cause of hospitalization for people with diabetes?
Diabetic foot ulcers
* Diabetes accounts for approximately half of all lower limb amputations every year due to infection.
* All people with diabetes should have regular foot exams.
35
What are the three main tests used to diagnose diabetes?
1. Fasting Plasma Glucose Test
2. Casual Plasma Glucose Test
3. Oral Glucose Tolerance Test (OGTT)
36
Describe the Fasting Plasma Glucose Test
* 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.
37
Describe the Casual Plasma Glucose Test
* 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.
38
Describe the Oral Glucose Tolerance Test (OGTT)
* This test is used when the other tests are unable to definitively diagnose diabetes.
* 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.
39
Describe Glycosylated Hemoglobin and how it's useful in testing for diabetes
* 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.
40
What is the primary goal of diabetes therapy?
maintain tight control of plasma glucose levels
41
What are the target plasma glucose levels?
o Pre-meal plasma glucose 4.0 - 7.0 mmol/L
o Peak post-meal glucose 5.0 - 10 mmol/L
o HbA1C < 7%
42
What are other treatment goals of diabetes therapy?
As diabetes is closely associated with cardiovascular disease and nephropathy, it is also crucial to decrease these risk factors:
Cardiovascular Risk
* Blood pressure – systolic < 130, diastolic < 80
* Lipids – LDL < 2.6 mmol/L, triglycerides < 1.7 mmol/L, HDL (men) > 1.0 mmol/L, HDL (women) > 1.3 mmol/L.
Kidney Function
* Urine albumin to creatinine ratio < 30 mg/g (albumin/creatinine).
43
Define nephropathy
Nephropathy is the deterioration of kidney function.
44
List the recommended lifestyle modifications for type 1 diabetes
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.
45
List the recommended lifestyle modifications for type 2 diabetes
Diet
* 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.
46
Briefly describe the discovery/history of insulin
* The effects of insulin were discovered by Sir Frederick Banting, a Canadian!
* Banting along with colleagues in Toronto won the 1923 Nobel prize in Physiology/Medicine for this incredible discovery.
* Before the discovery of insulin, patients diagnosed with diabetes would die within 2-3 years of diagnosis.
47
In terms of metabolic actions, insulin can be thought of as what?
anabolic (i.e., "building up" or conservative)
* This means that the actions of insulin promote energy storage and conservation.
48
Insulin's anabolic actions include what?
o Cellular uptake of glucose into liver, muscle, and fat.
o Glucose uptake results in the formation of glycogen (liver and muscle) and triglycerides (adipose tissue).
o Decreased hepatic gluconeogenesis (i.e. glucose synthesis).
o Cellular uptake of amino acids (mostly into muscle).
o Amino acid uptake results in increased protein synthesis.
49
Insulin deficiency puts the body into a _____ state.
catabolic (“breaking down”)
* This means the body favours the breakdown of complex molecules into simpler substances.
50
The catabolic effects seen in insulin deficiency include what?
o Glycogenolysis – conversion of glycogen to glucose.
o Gluconeogenesis – new glucose synthesis.
o 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!
51
How many types of insulin are available to treat diabetes?
7
52
Insulins can be separated based on time course of actions into which 4 categories?
o Short duration-rapid acting (lispro, aspart, glulisine)
o Short duration-slower acting (human)
o Intermediate duration (NPH, detemir)
o Long duration (glargine)
53
Which 3 different types of insulin are part of the short duration rapid acting insulin?
o Insulin lispro
o Insulin aspart
o Insulin glulisine
54
When are short duration rapid acting insulins administered?
This class of insulin is administered in association with meals to control the postprandial (i.e. after eating) rise in glucose.
55
What is the route of administration for short duration rapid acting insulins?
The route of administration is subcutaneous, although they may be used IV if required.
56
Describe the appearance of solution for all short duration insulins (rapid acting and slow acting)
They are supplied as a clear solution
57
What is the only type of short duration slower acting insulin?
unmodified human insulin
58
Describe how short duration slower acting insulins work
* 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.
59
What are the two intermediate duration insulins?
o Neutral Protamine Hormone (NPH) insulin
o Insulin Detemir
60
Can you use intermediate duration insulins at mealtime to control postprandial rises in blood glucose?
No, 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.
61
Why are the onset of action in both intermediate duration insulins delayed?
o NPH insulin – is insulin conjugated to protamine (a large protein). The protamine makes the molecule less soluble and decreases the absorption.
o Insulin Detemir – Insulin detemir molecules bind strongly to each other which delays absorption. (remember Module 2?)
62
How are intermediate duration insulins administered?
Both NPH insulin and insulin detemir are administered by subcutaneous injection.
63
Which insulin is supplied as a cloudy suspension?
NPH insulin
(All other insulins are a clear solution including insulin detemir and insulin glargine)
64
What is the only type of long-acting insulin?
Insulin glargine
65
What is the main advantage of insulin glargine?
The main advantage of insulin glargine is its long duration of action therefore, it is administered by subcutaneous injection only once daily at bedtime.
66
List some rule for mixing insulins
o Only NPH insulin can be mixed with short acting insulins.
o When the mixture is prepared, the short acting insulin should be drawn into the syringe first.
o Mixtures are stable for 28 days.
67
Define postprandial
during or relating to the period after dinner or lunch
68
Rapid decreases in blood glucose, such as in overdose, result in activation of the sympathetic nervous system which causes what?
o Tachycardia
o Palpitations
o Sweating
o Nervousness
* When blood glucose levels decrease more gradually, CNS symptoms such as headache, confusion, drowsiness, and fatigue occur.
69
The primary complication of insulin treatment is what?
hypoglycemia (blood glucose < 3mmol/L).
* If hypoglycemia is severe coma, convulsions, or even death may occur.
70
Describe the management of hypoglycemia
* 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.
71
What is glucagon?
* 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.
72
Glucagon is ineffective in which patients?
Glucagon is ineffective in starving or malnourished patients. Why? Malnourished or starving patients often do not have any glycogen stores to begin with.
73
Oral antidiabetic drugs are used to treat type _____ diabetes and are for the most part ineffective in type _____ diabetes.
2, 1
74
List the six classes of oral anti-diabetic drugs
1. Biguanides
2. Sulfonylureas
3. Meglitinides
4. Thiazolidinediones (glitazones)
5. Alpha-glucosidase inhibitors
6. Gliptins
75
What is often the (class of) drug of choice for treating type 2 diabetes?
Biguanides (metformin)
76
List the three separate ways in while biguanides lower blood glucose
1. Increases the sensitivity and number of insulin receptors.
2. Decreases hepatic gluconeogenesis.
3. Reduces intestinal glucose absorption.
77
What is the major advantage of biguanides?
they don’t increase insulin levels, so they pose no risk of hypoglycemia
78
List the adverse effects of biguanides
* 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).
79
What are the mechanisms of action of Sulfonylureas?
* Act primarily by stimulating release of insulin from the pancreas.
* They also inhibit glycogenolysis (the breakdown of glycogen to glucose).
80
There are “1st generation” and “2nd generation” sulfonylureas. The major difference between the two generations is what?
that second generation sulfonylureas are much more potent and cause fewer drug interactions
81
What is the major adverse effect of sulfonylureas?
hypoglycemia
* Additionally, prolonged use may cause pancreatic burnout (i.e. the pancreas has a reduced capacity to synthesize insulin).
82
What are the mechanisms of action of Meglittinides?
* Meglitinides have the same mechanism of action as sulfonylureas, as they stimulate insulin release from the pancreas.
83
How do meglitinides differ from sulfonylureas?
o Have a short half life so they are effective for treating postprandial rises in glucose.
o Less likely to cause hypoglycemia.
o Less likely to cause pancreatic burnout.
84
What are the mechanisms of action of Glitazones?
* 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 (remember Module 12?).
85
List the adverse effects of glitazones
o Fluid retention/edema
o Headache
o Myalgia
86
What are the mechanisms of action of Alpha-Glucosidase Inhibitors?
* 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.
87
List the adverse effects of Alpha-Glucosidase Inhibitors
* Adverse effects are limited to the intestine since alpha-glucosidase inhibitors are poorly absorbed.
* Adverse effects include:
o Flatulence
o Cramps
o Abdominal distention
o Diarrhea
o Decreased iron absorption
88
What are the mechanisms of action of Gliptins?
* 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.
89
List the adverse effects of Gliptins
Gliptins have no known major adverse effects
90
What are Incretin Mimetics?
* Incretin mimetics are synthetic incretin analogs that mimic the actions of incretin hormones (GLP-1 and GIP).
* Therefore incretin mimetics cause an increase in insulin release and a decrease in glucagon release.
91
How are Incretin Mimetics administered?
Incretin mimetics are administered by subcutaneous injection and are used as adjunctive therapy with biguanides or sulfonylureas.
92
List the adverse effects of Incretin Mimetics
o Hypoglycemia
o Pancreatitis (inflammation of the pancreas)
93
List all the drug treatments (classes) available to treat type 1 and type 2 diabetes
Short Duration, Rapid Acting
Lispro, Aspart, Glulisine
Short Duration, Slower Acting
Human Insulin
Intermediate Duration
NPH (Neutral Protamine Hormone)
Insulin Detemir
Long Acting Insulin
Insulin Glargine
Oral Anti-Diabetics (for Type 2)
-Biguanides
-Sulfonylureas
-Meglitinide
-Glitazones
-Alpha-glucosidase inhibitors
-Gliptins
SC administration (for Type 2)
Incretin Mimetics
