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Diabetes
1
Why is Diabetes Important?
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Why is Diabetes Important?
Source: 2004–2006 National Health Interview Survey estimates projected to year 2007
Why is Diabetes Important?
• Diabetes is probably the most important
endocrine disorder
• A lot of people have diabetes and it causes a lot
of healthcare issues
• Type 2 diabetes is increasing among children,
teens (10-19), and the elderly over 60
• Percent of people with diabetes, by age group
– 20-39 – 2.6%
– 40-59 – 10.8%
– 60 and older – 23.8%
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Type 2 Diabetes is Increasing in
Children and Teens, Especially in
Certain Groups
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Type 2 Diabetes is Increasing in Children and Teens,
Especially in Certain Groups
Source: SEARCH for Diabetes in Youth Study.
NHW=Non-Hispanic whites; AA=African Americans; H=Hispanics; API=Asians/Pacific Islanders; I=American Indians
Chronic Complications of Diabetes
Types 1 and 2
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Chronic Complications of Diabetes Types 1 and 2
1. Frequent infections
- The high level of blood glucose
acts as a fuel for microorganisms
2. Diabetic retinopathy
3. Diabetic nephropathy
4. Arteriosclerosis/
vascular disease
5. Diabetic neuropathy
•
•
One in four hospitalized patients
has diabetes
Problems two through five are
the most responsible for health
issues among diabetes
Porth, 2011, Essential of Pathophysiology,
3rd ed., Lippincott, p. 820
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Diabetes Mellitus
Types of Diabetes Mellitus
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Diabetes Mellitus
Types of Diabetes Mellitus
A. Type 1:
1. Beta cells of the pancreas are destroyed by autoimmune
attack.
2. No insulin is produced.
3. Must be treated with insulin injections in order to replace
what is not present
B. Type 2:
1. Insulin resistance
2. They have insulin but there is inadequate insulin secretion
in order to control blood sugar
3. May be treated with diet and exercise, oral medications,
and/or insulin injections
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Lecture Outline
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Lecture Outline
I.
Insulin Pathways in Liver, Muscle and Fat
II.
Pathophysiology of Diabetes Mellitus
II.
Symptomatology of Diabetes Types 1 and 2
III. Insulin Therapy: Focus on Type 1
IV. Adverse Effects of Insulin
V.
Pramlintide Therapy
VI. Pregnancy in Type I Diabetes
VII. Type 2 Diabetes: Pathophysiology and Presentation
VIII. Drugs Primarily Targeting Type II Diabetes
IX. Pregnancy in Type 2 Diabetes
X.
Gestational Diabetes
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Diabetes and Insulin Therapy
Diagram
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Diabetes and Insulin Therapy
Diagram
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Insulin Pathways in the Liver
Diagram
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Insulin Pathways in the Liver
Diagram
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Insulin Pathways in the Liver
Description
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Insulin Pathways in the Liver
Description
• This is a liver cell
• Liver takes up glucose
– Can use it in the TCA cycle and make ATP
– Can store it as glycogen (the storage form of glucose)
• When we eat and blood sugar is high, insulin is high, the liver takes
in glucose and stores it as glycogen
• When we are fasting, blood sugar is getting low, insulin is low, and
the pathway that is promoted by insulin is not going forward
– Glycogen is being broken down and the liver can add glucose back to
the blood stream to nourish the body
• The liver, under the guidance of insulin, controls blood glucose in
the body by breaking down glycogen or taking glucose out of the
body
– Insulin inhibits this pathway
• Therefore, this pathway does not go forward unless insulin is low
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Gluconeogenesis
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Gluconeogenesis
• The liver can make new glucose and add it to
the bloodstream
– Would want the liver to do this when glucose is
low
– The pathway is inhibited by insulin
• The pathway is not activated after eating when insulin
is high
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Synthesis of Triglycerides
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Synthesis of Triglycerides
• Insulin also promotes the synthesis of triglycerides from fatty acids
– Triglycerides are the storage form of fat
• Want to store fats after you have just eaten
– When fasting, triglyceride pathway is not being promoted, fats are
broken down and made into acetyl-CoA
– Can be used to form ketone bodies
• Ketone bodies get into the circulation and go throughout the body and then
are turned back into acetyl-CoA
• The pathway for the synthesis of ketone bodies is inhibited by insulin
– Insulin is high after eating - can use glucose to fuel the body so insulin is inhibitory for
the production of glucose
– The liver itself cannot use ketone bodies
• After not eating for a while, blood sugar would be low and ketone
bodies would be present in the urine
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Insulin Pathways in the Muscle
Diagram
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Insulin Pathways in the Muscle
Diagram
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Insulin Pathways in the Muscle
Description
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Insulin Pathways in the Muscle
Description
• Muscle cells take up glucose and can use it for fuel for
the Kreb’s cycle
• Muscle cells store glycogen because they are energetic
cells that need a lot of glucose
– The glucose used by the muscle cells comes from the liver,
gluconeogenesis, and the muscle cell’s own storage
• The difference between the muscle and the liver is that
in the muscle insulin must be present in order for
glucose to be taken up by the muscle
– Glucose can also be taken up by the muscle cell when the
cell is exercising
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Insulin Pathways in Fat Tissue
Diagram
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Insulin Pathways in Fat Tissue
Diagram
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Insulin Pathways in Fat Tissue
Description
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Insulin Pathways in Fat Tissue
Description
• Glucose entry into fat cells is insulin-dependent
• The fat cell is the storage place for triglycerides
• The pathway of taking triglycerides into the fat is promoted
by insulin
– In people with type 1 diabetes, insulin is not produced, so
triglycerides are not taken into the fat cells
• This explains why people with type 1 diabetes often lose weight
before being diagnosed and gain weight when they go on insulin
• If you just ate, triglyceride levels will be high and insulin will
be high
– When insulin is high, the body does not want/need to be
breaking down fats because you have dietary fat
– When insulin is lower, then you will break down the fats
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Glucose, Amino Acid, and Free Fatty
Acid Utilization by Muscle, Liver, and
Fat Cells
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Glucose, Amino Acid, and Free Fatty Acid Utilization by Muscle, Liver, and Fat Cells
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In the liver, what is the name of the
pathway that generates new glucose
molecules from 3-carbon
fragments?
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In the liver, what is the name of the pathway that generates
new glucose molecules from 3-carbon fragments?
25%
25% 25% 25%
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Glycogen breakdown
Glycogen synthesis
Gluconeogenesis
Glycogenolysis –
glycogen breakdown
G
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1.
2.
3.
4.
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Ways of Measuring the Effect of
Insulin
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Ways of Measuring the Effect of Insulin
1. Urine testing for glucose or ketones:
a) Urine testing for glucose is no longer recommended.
b) Presence of ketones in the urine signifies fat breakdown
2. Blood Sugar: blood testing for glucose is the most accurate.
a) Normal fasting BS – 80-110 mg/dl
b) Normal 2-hr post prandial (2 hr PP) <160 mg/dl
- The person drinks a bottle of glucose
- Come in, measure blood glucose, drink bottle of glucose
solution, and then measure blood glucose again
3. Hemoglobin A1c : indicates about a 3-months average glucose level.
a) Normal Hb A1c is about 5%.
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Hemoglobin A1C
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Hemoglobin A1C
Glucose + protein (i.e., hemoglobin)
Glycosylated protein (i.e., hemoglobin A1C)
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The Basis of Hemoglobin A1C
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The Basis of Hemoglobin A1C
• If you take a protein (ex. albumin) and sit it in glucose,
some of the glucose molecules will hitch onto the proteins
• In the bloodstream, the glucose molecules are also being
hitched onto proteins
• Use hemoglobin because we know that the average
lifespan of a red blood cell is 120 days
– The average age of a red blood cell is 60 days
– The degree of glycolyslation is indicative of the average blood
sugar concentration over the last 60 days because the
hemoglobin has been in the glucose for an average of 60 days
• Shows how well the blood sugar has been controlled over the past 60
days
• Normal is about 5%
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Rate of Daily Self-monitoring of
Glucose among Diabetic Adults
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Rate of Daily Self-monitoring of Glucose among Diabetic Adults
MMWR November 2, 2007 / 56(43);1142
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Diabetic Symptomatology
Presenting Symptoms of Type 1
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Diabetic Symptomatology
Presenting Symptoms of Type 1
1. Polyuria (frequent peeing) – the sugar in the urine
acts similar exerts osmotic pressure, keeping the
water in their urine
2. Polydipsia (frequent thirst)– dehydrated from peeing
all of the time
3. Polyphagia (fat or muscle cells cannot take up
adequate glucose because insulin is not present)
4. Possibly DKA.
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Sources of Insulin
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Sources of Insulin
I. Beef or pork: no longer manufactured.
- Not used now because people developed allergies to
them
II. Human insulin is produced recombinately in yeast and is
identical to that produced by the pancreas (in those of us who
do not have type 1 diabetes).
III. Mutated human insulins (Lehne calls them “modified”
insulins), produced recombinately in yeast, have different
pharmacokinetic properties from unmutated human insulin.
- This alters their pharmocokinetic properties
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Insulin Strength and Dose
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Insulin Strength and Dose
I. Insulin is measured in units: this is a biological measurement
that tells how much a given quantity of insulin will lower blood
sugar in a test animal.
II. Insulin preparations are in a concentration of 100 units/ml. Use
an insulin syringe to inject. Some insulin come in a prefilled
injection pen in addition to being available in a vial.
- ex. the flex pen is advertised heavily on television
•There is no set dose of insulin: each patient uses the amount that
controls his/her blood sugar.
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Types of Insulin
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Types of Insulin
INSULIN TYPE
APPEARANCE
ADDED
PROTEI
N
PROFILE OF
ACTION(hrs)*
ONSET
PEAK
DURATION
Lispro clear (pump use)
none
0.2-0.5
1.5-2
3-5
Aspart clear (pump use)
none
0.2-0.5
0.5-1
3-5
Glulisine clear (pump use)
none
0.2-0.5
1-1.5
1.5-2.5
none
0.3-0.7
2-4
5-12
protamin
e
1-2
6-12
18-24
None
~1.5
N/A
~16-24
Short duration: rapidacting
Short duration: slower
acting
Regular clear (IV or SC)
Intermediate-acting
NPH cloudy
Insulin demetir Clear (not used
IV)
Long-acting
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Categories of Insulin
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Categories of Insulin
• Rapid-acting acts very quickly
– They are all modified insulins that have a different structure that makes them
easier to be absorbed form the subcutaneous tissue
• Most insulin is injected subcutaneously
• Short-duration
• The mutant insulins are much more expensive but they can be injected
right before or right after eating, rather than 20 minutes before eating
• Because NPH is bound to the protamine, it has a longer onset and
duration
• Long-acting
• Some of these can be used in the insulin pump
– The pump is warm and there used to be precipitation in the tubing, but now it
is okay
• THE ONLY INSULIN THAT IS USED IN AN IV IS REGULAR INSULIN --- this
will be on the test!!!!!
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Profiles of Action of Various
Insulins
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Profiles of Action of Various Insulins
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Lehne, 2009, Pharmacology for Nursing Care, 7th ed., Elsevier, p. 666
Profiles of Action of Insulin and
Insulin Analogs
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Profiles of Action of Insulin and Insulin Analogs
Hirsch, 2005, Insulin analogs, NEJM, 352:174-83
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Insulin Mixtures
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Insulin Mixtures
• 70/30 insulin lispro protamine/lispro
• 75/25 insulin aspart protamine/aspart
• 70/30 NPH/regular
• 50/50 NPH/regular
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Insulin Administration
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Insulin Administration
I. Subcutaneous:
All preparations
II. Intravenous:
Regular insulin only
III. Inhalation:
Regular insulin only
(The only available inhaled insulin
formulation has been taken off the
market.)
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Constant Insulin Infusion Pump
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Constant Insulin Infusion Pump
•A beeper-sized device containing a motor-driven syringe that
the patient fills with a short-acting insulin (regular, lispro,
aspart or glulisine).
•Tubing from the syringe is connected to a needle the patient
implants in the subcutaneous space.
•The patient sets the device to deliver a basal level of insulin
constantly, and can instruct it to deliver boluses to take care of
meals.
•The pumps are becoming very sophisticated
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Which insulin can be used IV?
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Which insulin can be used IV?
25%
PH
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iti
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25% 25% 25%
ro
Lispro
Demitir
Regular
NPH
Li
sp
1.
2.
3.
4.
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The Goal of Insulin Therapy
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The Goal of Insulin Therapy
• Euglycemic (normoglycemic) control: defined
as blood sugar control that approximates that of a
person without diabetes (normalization of blood
sugar).
• Virtually all newly diagnosed Type 1 diabetic
patients are placed on this type of therapy
because of the evidence that it decreases
complications of diabetes.
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Effect of Intensive vs. Conventional
Insulin Therapy
on Development of Complications
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Effect of Intensive vs. Conventional Insulin Therapy
on Development of Complications
The effect of intensive treatment of diabetes on the development and progression of long-term complications in
insulin-dependent diabetes mellitus. N. Eng. J. Med., 329: 1993, p. 981
Effect of Intensive vs. Conventional
Insulin Therapy
on Development of Complications
Description
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Effect of Intensive vs. Conventional Insulin Therapy
on Development of Complications
Description
• Compares the blood sugar testing with the goal of
normal glucose values with the old method of urine
testing and the fixed insulin regimen (conventional
therapy)
– The graphs showed retinopathy in patients
• More patients in the conventional treatment has retinopathy than
in the new treatment
• This trial revolutionalized the treatment of diabetes
• The goal to control the blood sugar as though the
person is not diabetic has been shown with both type I
and type II (more so type I) to reduce the complications
associated with diabetes
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Strategies for Insulin Therapy
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Strategies for Insulin Therapy
1. Multiple insulin injections.
2. Constant insulin infusion pump.
• With each strategy, patients must test their
blood sugar 4-10 times per day, and make
adjustments in their insulin dose based on their
blood sugar measurements.
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Strategies for Multiple Insulin
Injections
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Strategies for Multiple Insulin Injections
Shade, et al, Intensive Insulin Therapy, Excerpta Medica, 1983, p. 133.
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The Choice of Insulin Strategy is
Based on Patient Preference
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The Choice of Insulin Strategy is Based on
Patient Preference
• The pump may be harder to use and require
more patient motivation and commitment.
• Either strategy requires an intelligent patient
with a good knowledge of their own disease.
• Children and elderly patients may have
problems related to their stage of development
or comorbidities.
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Comparison of Pump and Multiple
Insulin Injections
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Comparison of Pump and Multiple Insulin Injections
The pump and multiple insulin injections both produce similar
results when used optimally. The choice between the two is based
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on patient preference.
Insulin Use Across the Lifespan
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Insulin Use Across the Lifespan
• Children need close supervision but most prefer to prick their
own fingers and give their own injections as soon as they are able.
• Adolescents may rebel against the dietary restrictions and the
need for continual monitoring.
• Elderly may have difficulty with seeing test strips or manipulating
syringes because of retinopathy or neuropathy.
• Cognitive decline in the elderly may necessitate someone else
taking responsibility for the insulin regimen.
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Individualization of Insulin
Protocols
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Individualization of Insulin Protocols
•Each patient’s regimen is shaped by their lifestyle, their
blood sugar measurements, and their diet—but for type 1
diabetes, each patient’s goal should be euglycemia.
•For type 2, the goal may be able to be a little bit
above normal because the data supporting the benefit
of euglycemia are not as strong in type 2 diabetics as
in type 1 diabetics
•Patients are instructed in a basic insulin regimen and
given instructions on what to do in case of particular
blood sugar measurements—this is called a sliding scale.
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Example of a Sliding Scale
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Example of a Sliding Scale
Fasting blood sugar
60-80
Dose of regular insulin before
breakfast
20 units
80-100
25 units
100-120
30 units
120-130
35 units
130-140
40 units
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Adverse Effects of Insulin
Hypoglycemia
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Adverse Effects of Insulin
Hypogylcemia
Hypoglycemia: means low blood sugar
Two sets of symptoms
A. CNS symptoms: headache, confusion, drowsiness, and
fatigue followed by coma, seizures, and possibly death.
B. Peripheral symptoms: tachycardia, sweating, nervousness,
all caused by activation of the sympathetic nervous system.
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Treatment for Hypoglycemia
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Treatment for Hypoglycemia
•If conscious: p. o. sugar, i.e. a sugar cube, cake icing,
glucose tablets, etc.
•If unconscious: IV dextrose (glucose), 50 g.
•If confronted with an unconscious diabetic patient, it
is safest to assume that the problem is hypoglycemia
and administer IV dextrose immediately.
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Problematic Drug Interactions for
Diabetics
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Problematic Drug Interactions for Diabetics
•Beta-blockers may mask the sympathetic
symptoms of hypoglycemia.
•Other drugs that affect blood sugar or insulin
resistance may increase or decrease the activity
of insulin.
•Oral drugs for diabetes
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To maintain euglycemic control,
what measures must a diabetic
patient use to measure his/her
blood sugar?
91
To maintain euglycemic control, what measures must
a diabetic patient use to measure his/her blood
sugar?
25%
1. Urine testing
2. Home blood sugar
testing once a day
3. Home blood sugar
testing 4-6 times per
day
4. Hemoglobin A1C testing
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Amylin A
The Basis for a Drug for Type 1 and
Type 2 Diabetics
93
Amylin A
The Basis for a Drug for Type 1 and Type 2 Diabetics
•What is amylin?
•Amylin is a small protein that is made in the beta cells
of the pancreas (just like insulin) and stored in
secretory granules along with insulin.
• When insulin is secreted, amylin is secreted along
with it.
•Until recently, we didn’t know the function of amylin.
•BUT in type 1 DM, the beta cells die so there is no
amylin!, just like they do not have any insulin
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Functions of Amylin
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Functions of Amylin
1. Potentiates the action of insulin on target cells.
2. Inhibits the secretion of glucagon (a pancreatic hormone
that is made in alpha cells of the pancreas that opposes
insulin).
3. Delays gastric emptying and thereby blunts postprandial
blood glucose peaks because the food does not get into the
intestines all at once, but rather does it slowly
4. Increases satiety and promotes weight loss.
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Secretion Profile of Amylin and
Insulin in Healthy Adults
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Secretion Profile of Amylin and Insulin in Healthy Adults
Symlin® prescribing information
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Pramlintide (Symlin®)
An Amylin Agonist
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Pramlintide (Symlin®)
An Amylin Agonist
• A small protein very similar to amylin.
• Inject subcutaneously before meals
(cannot be mixed with insulin).
• For injection, a 30 unit (0.3 ml) insulin
syringe is used and a conversion chart tells
what volume to draw up.
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Conversion of Symlin Dose to Insulin
Unit Equivalents
101
Conversion of Symlin Dose to Insulin Unit Equivalents
102
Starting a Type 1 Patient on
Pramlintide
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Starting a Type 1 Patient on Pramlintide
•Because pramlintide potentiates the does of insulin, it
decreases their previous dose of short-acting insulin by
half.
•Start pramlintide at 15μg before major meals.
•If nausea occurs, continue that dose until it subsides
(several days); then increase in 15 μg increments to 60
μg, each time waiting for nausea to subside.
•After a stable dose is achieved at which there is no
nausea, adjust the insulin dose to achieve euglycemic
control.
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Problems with Pramlintide
105
Problems with Pramlintide
1. Delayed absorption and lower peak levels of po
drugs due to delayed gastric emptying (take them
one hour before injecting pramlintide).
2. Should not be used with other drugs that delay
gastric emptying or slow GI motility.
3. Potentiates insulin’s ability to cause hypoglycemia,
increasing the risk of hypoglycemia
4. Nausea and vomiting are prominent side effects that
may abate with continued use.
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Mean Plasma Glucose Concentration
in Type 1 DM Patients on Regular
Insulin Compared with Pramlintide
plus Regular Insulin
107
Mean Plasma Glucose Concentration in Type 1 DM Patients on
Regular Insulin Compared with Pramlintide plus Regular Insulin
Symlin® prescribing information
108
Possible Problems for Pregnant
Diabetics
109
Possible Problems for Pregnant Diabetics
1. Increased incidence of birth defects.
- This is possibly because insulin is a
growth factor
2.
Premature labor that may be related to the
maturation of the placenta
3.
Fetal macrosomia (big body) and
organomegaly (big organs)
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Infants of Diabetic Mothers
111
Infants of Diabetic Mothers
1. Glucose crosses the placenta.
2. Fetal pancreas responds to hyperglycemia by secreting high levels of
insulin.
- If the mother’s glucose is high, the baby’s pancreas will pour out
insulin to decrease glucose, but it cannot because the glucose comes
from the mother
3. Insulin stimulates fat deposition in infant, causing macrosomia.
4. Insulin stimulates glycogen deposition in infant, causing
organomegaly.
5. Fetal hyperinsulinemia continues after delivery.
- But when maternal glucose supply is cut off, this results in perinatal
hypoglycemia because the glucose is no longer present
112
Pregnant Patients with Preexisting Type 1 DM
113
Pregnant Patients with Pre-existing Type 1 DM
1. Insulin requirements decrease at first and then
continually increase as the pregnancy progresses.
2. With ideal control, fetal outcomes approach those of
nondiabetic mothers.
3. Infants may require Caesarean section because of
macrosomia and also should be monitored closely for
hypoglycemia after birth.
4. Gestational and type 2 DM will be discussed later.
114
Type 2 Diabetes
115
Type 2 Diabetes
•Part of a syndrome that includes insulin
resistance.
•People develop worsening insulin resistance
over their lifetime and type 2 diabetes may be the
result.
•However, if people with insulin resistance take
care of themselves and/or avoid weight gain, they
can delay the onset or prevent type 2 diabetes.
116
What is Insulin Resistance?
Diagram
117
What is Insulin Resistance?
Diagram
118
Nestler, J.E., Assessment of insulin resistance. Scientific American Science and Medicine, 1: 1994, p. 59.
Insulin Resistance
119
Insulin Resistance
• The artificial pancreas machine was set to maintain
their plasma insulin and glucose at 80mg
– The insulin directed the cells to take up the glucose
• For the normal people, the machine had to give a lot of
glucose to maintain insulin, but for the hypertensives,
the machine did not have to give as much glucose
– The insulin was having greater effects on the controls than
on the hypertensives
• The hypertensive patients had insulin resistance and insulin did
not work as well as in normal people
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Explanation of Insulin Resistance
Slide
121
Explanation of Insulin Resistance Slide
• Two groups were compared – hypertensives and people
without hypertension.
• The subjects were hooked up to an “artificial pancreas” in the
hospital. The machine can be set to maintain constant insulin
and glucose levels in the subject.
• The machine was set to maintain a plasma insulin level of 80
μU/ml and a plasma glucose of 80 mg/dl
• Dextrose (glucose) was delivered through an IV line to
maintain the plasma glucose at 80 mg/dl.
• The normal subjects required higher quantities of dextrose via
IV to maintain their blood sugar at 80 mg/dl than the
hypertensive patients did.
– Because their insulin was working better, whereas the hypertensives
had insulin resistance
Explanation of Insulin Resistance Slide (cont.)
• The reason the normal subjects required more IV glucose
was that the infused insulin was promoting glucose
removal from the bloodstream
– The removed glucose was being stored in the liver as glycogen or
was entering fat and muscle cells.
– Because it was removed from the bloodstream, in order for the
subjects’ blood sugar to remain at 80 mg/dl, the machine replaced
the removed glucose with the dextrose infusion.
• In this experiment, the insulin infusion was more effective
at causing glucose to be removed from the bloodstream in
normal subjects than in the hypertensive subjects.
• The hypertensive subjects had insulin resistance.
Known Mediators of Insulin
Resistance
124
Known Mediators of Insulin Resistance
I. Acute:
A. Cortisol increases insulin resistance
B. Growth Hormone increases insulin resistance
C. Epinephrine - increase
D. Hyperinsulinemia - increase
E. Hyperglycemia - increase
II. Chronic:
A. Receptor-mediated: Fewer insulin receptors on each
cell (common in obesity)
- as you gain weight, the number of insulin receptors on
cells decreases, and if you lose weight the number
increases
B. Postreceptor: Second messenger system doesn’t work
properly
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Insulin Receptor Activation
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Insulin Receptor Activation
Porth, 2007, Essential of Pathophysiology, 2nd ed., Lippincott, p. 703
127
Insulin Receptor Activation
Description
128
Insulin Receptor Activation
Description
• When insulin binds to the receptor, the signaling
proteins cause a number of effects within the cell
– In post-messenger resistance, there is most likely
something wrong inside of the cell
– When insulin binds to its receptor, GLUT-4 becomes
available to transport insulin
• If there is a post-receptor problem, there will
most likely be a problem in glucose and fat
transport
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The “Metabolic Syndrome”
130
The “Metabolic Syndrome”
•A.K.A “syndrome X” or “diabesity”
• Central obesity, hypertension, poorly regulated blood
glucose, and dyslipidemia
• A recent article states that ~1 in 3 Americans has the
metabolic syndrome.
• Not everyone with the metabolic syndrome develops type 2
DM, but such people are at increased risk when compared to
people without the metabolic syndrome.
• Lifestyle changes can delay or prevent type 2 DM.
131
Progression of Insulin Resistance to
Type 2 DM and Beyond
Diagram
132
Progression of Insulin Resistance to Type 2 DM and Beyond
Insulin
Sensitivity
Normal glucose
tolerance
Insulin
Secretion
Diabetic
HIGH
NORMAL
LOW
Nonobese
Normal
Obese
Normal
Obese,
Impaired
Glucose
Tolerance
Obese,
Diabetic
Hyperinsulinemic
Adapted from Nestler,JE, Assessment of Insulin Resistance,Science & Medicine, 1: 1994,
p.58.
Obese,
Diabetic
Hypoinsulinemic
13
3
Progression of Insulin Resistance to
Type 2 DM and Beyond
Description
134
Progression of Insulin Resistance to Type 2 DM and Beyond
Description
• A normal person who is not fat has normal insulin sensitivity or
secretion
• If the same person is fat, sensitivity decreases (resistance increases)
and the pancreas secretes more insulin
– The pancreas continues to increase the secretion of insulin in order to
control the blood sugar
• Fasting blood glucose is normal, but if given a glucose load (drink), the blood
sugar will be too high
– This is referred to as impaired glucose intolerance
» Normally are fine, but if they has a lot of glucose, the pancreas cannot compensate
• As the person ages, the secretion of insulin drops. It is still greater than
normal, but it is not enough to control the fasting blood sugar. The person now
has diabetes
– The obese, diabetic hyperinsulinemic person can usually be treated with oral
medications
• The obese, hypoinsulinemic person may have to receive insulin because they
do not have enough
• With this bar graph, you can go forward and backward!
– This is a good thing because the person can go back to normal (from
obese, impaired)
• Do not think that you can go all the way from obese, diabetic, hypoinsulinemic
to normal
135
Commonalities of Type 2 Diabetes
136
Commonalities of Type 2 Diabetes
1. Pancreatic secretion of insulin is not sufficient to control
blood sugar.
- Insulin secretion may be very high, higher than in a
normal person, but it cannot control the glucose
because of the resistance
2. Receptor-mediated and postreceptor insulin resistance.
- could be due to mutations on the proteins/receptors
3. Gluconeogenesis is not appropriately inhibited by insulin.
137
Type 2 DM is Composed of Multiple
Vicious Cycles
Diagram
138
Type 2 DM is Composed of Multiple Vicious Cycles
139
Vicious Cycles of Diabetes
140
Vicious Cycles of Diabetes
• The type 2 people have several cycles that are
working against them to make type 2 diabetes
worse
– Obesity – downregulation – resistance –
hyperglycemia – resistance
– High insulin – downreg. – resistance
– Insulin – increased deposition of fat – obesity –
downreg. – resistance
– Decrease in pancreatic responsiveness –
hyperglycemia
– Gluconeogenesis – hyperglycemia
141
Presentation of Type 2 DM
142
Presentation of Type 2 DM
1. Most Type 2 patients are older and/or obese.
- The age of onset is decreasing due to obesity
2. Present with complications of diabetes: fungal infections,
UTI, vascular disease, etc.
3. Blood sugar may not be high enough for symptoms of
polydipsia, polyuria, or polyphagia.
4. Evidently the amount of insulin present prevents ketosis and
DKA.
143
Overview of Treatment for Type
2
144
Overview of Treatment for Type 2
1. Diet and exercise is the cornerstone treatment
- Diet is even more important in type 2 than in type
1
2. Oral agents.
3. Insulin for those whose diabetes cannot be controlled
with oral agents.
4. Home glucose monitoring is used for patients in all
stages of type 2.
145
Diet and Exercise
146
Diet and Exercise
• They are the cornerstone of treatment.
• Diet lowers blood sugar and helps with weight
loss.
• Exercise lowers blood sugar without need for
insulin and burns calories to help with weight loss
• These strategies may be sufficient for mild
cases.
147
Therapy for Type 2 Diabetes Must
Address Defective Metabolic
Processing Pathways
148
Therapy for Type 2 Diabetes Must Address Defective
Metabolic Processing Pathways
149
Drugs for Type 2 DM to Increase the
Secretion of Insulin – Sulfonylurea
Drugs
150
Drugs for Type 2 DM to Increase the Secretion
of Insulin – Sulfonylurea Drugs
I. Most have a chemical structure called sulfonylurea.
II. Stimulate “nonphysiologic” secretion of insulin
independent of blood glucose concentrations. They can
cause hypoglycemia.
- if you have not eaten, insulin will go up
III. Block an ATP-dependent potassium channel,
preventing repolarization of the beta cell when the beta
cell is depolarized and is secreting insulin
151
Mechanism of Action of the
Sulfonylurea-like Drugs
152
Mechanism of Action of the Sulfonylurea-like
Drugs
Porth, Pathophysiology: Concepts of Altered Health States, 7th ed., 2005, Lippincott, Williams & Wilkins, p.990.
153
Drugs which Increase Insulin
Secretion by Inhibiting ATP-sensitive
K+ Channels
154
Drugs which Increase Insulin Secretion by Inhibiting
ATP-sensitive K+ Channels
•1st generation sulfonylureas:
Acetohexamide
Chlorpropamide
Tolazamide
Tolbutamide
•2nd generation sulfonylureas are the ones that are used
Glipzide
Glyburide – the only one that is safe for pregnancy
Glimepiride
• Meglitinides (non-sulfonylurea, short acting) are used for meal control
•Take them right before you eat and increase the secretion of insulin right before
the meal and then they are metabolized quickly
Repaglinide
Nateglinide
155
More on Meliglitinides
Repaglinide and Nateglinide
156
More on Meliglitinides
Repaglinide and Nateglinide
• Meliglitinides have been shown to interact with gemfibrozil,
a lipid-lowering drug and with antifungals like ketoconazole
and itraconazole, at the level of cytochrome P450 enzymes.
•Metabolism of repaglinide and nateglinide may be delayed so
that they reach higher plasma levels and have prolonged
activity.
•Hypoglycemia may result.
157
Adverse Effects and
Contraindications of SulfonylureaLike Drugs
158
Adverse Effects and Contraindications of SulfonylureaLike Drugs
1.
Hypoglycemia due to the non-physiologic secretion of insulin
regardless of the blood glucose levels
2.
Hepatotoxicity (elevated liver enzymes).
3.
Patients with liver disease may metabolize these drugs more slowly,
which will produce longer half-lives and higher peak concentrations.
4.
Elderly patients with impaired renal function might also have
slowed elimination.
5.
N and V, rashes. (universal adverse effects)
6.
Contraindicated in type 1, since the patient does not have insulin.
7.
Contraindicated in pregnancy because of concerns about
teratogenicity (except for glyburide).
159
Therapy for Type 2 Diabetes Must
Address Defective Metabolic
Processing Pathways
160
Therapy for Type 2 Diabetes Must Address Defective
Metabolic Processing Pathways
161
Addressing the Cycle
162
Addressing the Cycle
• Work by increasing insulin secretion
– However, this will lead to the increased deposition
of fat
• This is a big problem, because then it increases the
vicious cycle of obesity
– These drugs are not used as often because there
are better drugs
163
Drugs That Affect Insulin
Resistance
164
Drugs That Affect Insulin Resistance
Two Chemical Classes:
A. Biguanides
B. Thiazolidinediones (glitazones)
165
Biguanide
Metformin
166
Biguanide
Metformin
•
•
Very widely used and good
Decreases glucose production by the liver, increases glycogen
synthesis, increases glucose utilization by fat and muscle, and
inhibits lipolysis.
•
Insulin also does these
•
We don’t know how metformin does these things, but it does not
do them by binding to the insulin receptor.
•
Can be used as monotherapy or in combination with a sulfonylurea
or a glitazone.
167
Adverse Effects of Metformin
168
Adverse Effects of Metformin
• May cause lactic acidosis in patients with any degree
of renal impairment, which slows elimination of
metformin and causes increased blood levels.
• This is very serious
169
Beneficial Effects of Metformin
170
Beneficial Effects of Metformin
• When used alone, it will not cause
hypoglycemia because it does not affect the
amount of insulin, it just makes its secretion
more effective
• When used as monotherapy, will not cause
weight gain.
171
Patients with Renal Impairment?
172
Patients with Renal Impairment?
•People that should not be given metformin
•Elderly.
•Diabetic.
•Patients receiving contrast for radiologic procedures,
such as angiography. Metformin must be withheld for
several days prior to the procedure.
•This is because the contrast causes renal
impairment and may lead to lactic acidosis
173
Other Problems with Metformin
174
Other Problems with Metformin
•Hepatic dysfunction may predispose the patient to
lactic acidosis.
•Nausea
•Vomiting
•Rashes
•Metallic taste
•One of the reasons that people stop taking
metformin
175
Thiazolidinediones(glitazones)
Mechanism of Action
176
Thiazolidinediones(glitazones)
Mechanism of Action
I. Pioglitazone
II. Rosiglitazone (Avandia)
• They interact with PPAR-gamma, a transcription factor
important in differentiation of fat and muscle cells.
• In some way, this improves insulin sensitivity, thus
decreasing insulin resistance and decreasing blood sugar
• These drugs are sometimes called “insulin sensitizers”.
177
Thiazolidinediones (glitazones)
Uses and Advantages
178
Thiazolidinediones (glitazones)
Uses and Advantages
•May be used as monotherapy, or combined with a
sulfonylurea, metformin, or insulin.
•Will not cause hypoglycemia when used alone because
they do not affect insulin secretion
•Resumption of ovulation in anovulatory patients.
•Ex. people with polycystic ovary syndrome (need to
be aware of this in some people, because some
diabetics may not want to ovulate)
179
Thiazolidinediones (glitazones)
Adverse Effects
180
Thiazolidinediones (glitazones)
Adverse Effects
•Both pioglitazone and rosiglitazone cause edema which may
worsen heart failure
•Half-lives of both may be prolonged in patients with hepatic
disease.
• A previous member of this class (troglitazone) was
removed from the market because of hepatotoxicity. This is
probably not a concern with current drugs.
•Possible cytochrome P450 interaction with birth control pills
(probably not rosaglitazone).
•The person may need to get a higher dose or use an
alternative method of contraception
181
Safety of Rosiglitazone (Avandia)
182
Safety of Rosiglitazone (Avandia)
• Although both rosiglitazone and pioglitazone have been
shown to cause increased fluid retention and to
exacerbate heart failure, a good bit of data suggests that
rosiglitazone is worse in this regard than pioglitazone.
– Rosiglitazone may be associated with increased cardiac
morbidity and mortality due to heart failure
• The FDA has issue the following recommendations.
– Restrict the use of the diabetes drug rosiglitazone (Avandia) to
patients with Type 2 diabetes who cannot control their diabetes
on other medications and are unable to take pioglitazone
– GSK (the marketer) will develop a plan for restricted access to
rosiglitazone
• Stay tuned
Therapy for Type 2 Diabetes Must
Address Defective Metabolic
Processing Pathways
184
Therapy for Type 2 Diabetes Must Address Defective
Metabolic Processing Pathways
185
Oral Drug Combinations
186
Oral Drug Combinations
Glipizide/metformin
2 dosages
Glyburide/metformin
2 dosages
Rosiglitazone/metformin
3 dosages
(Presumably will also have restricted access)
Pioglitazone/metformin
2 dosages
187
The Problem with Oral Drug
Combinations
188
The Problem with Oral Drug Combinations
•With combinations, the likelihood of
hypoglycemia may be increased.
•This is especially true with combinations of
metformin with a sulfonylurea-like drug.
189
Alpha-Glucosidase Inhibitors
Ascarabose and Miglitol
190
Alpha-Glucosidase Inhibitors
Ascarabose and Miglitol
• These drugs prevent the absorption of sugars in the intestine by inhibiting the
enzymes that degrade disaccharides (sucrose or lactose) to monosaccharides
(glucose, galactose, and fructose).
•Lactose – glucose and galactose
•Those with lactose intolerance do not have the enzyme that breaks
lactose into glucose and galactose, enzyme stays in the intestine, exerts
osmotic pull, leads to a lot of gas
•Sucrose – glucose and fructose?
• Disaccharides cannot be absorbed by the intestine.
• Since the disaccharides stay in the intestine, they provide increased food for
bacteria, which produce a lot of gas and cramping
• The disaccharides also increase the osmotic pressure of bowel contents,
increasing the liquidity of the stool.
•The drugs lead to lactose and sucrose intolerance, causing the symptoms of
lactose intolerance
191
Alpha-Glucosidase Inhibitors
Side Effects and Use
192
Alpha-Glucosidase Inhibitors
Side Effects and Use
Side Effects
Diarrhea
Flatulence
•Antidiabetic activity is modest—these drugs are
adjuncts to other treatment, not primary treatment.
• Used in type 1 and type 2.
193
Effects of Classes of Diabetes
Drugs
194
Effects of Classes of Diabetes Drugs
195
Porth, 2011, Essential of Pathophysiology, 3rd ed., Lippincott, p. 814
Exenatide (Byetta®)
196
Exenatide (Byetta®)
1.
A peptide drug that is an analog of a hormone called GLP-1 (a GLP-1 agonist).
2.
Potentiates glucose-sensitive insulin secretion.
- When your blood sugar is high, the pancreas secretes insulin and this drug
will potentiate it so that it secretes more insulin
- When the blood sugar is low, it will not do anything, so it will not cause
hypoglycemia
3.
Slows gastric emptying.
4.
Approved for use with metformin, sulfonylureas or glitazones.
5.
Not approved for type 1 (depends on pancreatic insulin secretion for
effectiveness)
- Because type 1 does not have a pancreas that can secrete insulin
197
Exenatide (Byetta®)
Administration and Interactions
198
Exenatide (Byetta®)
Administration and Interactions
• Administered by subcutaneous injection 1 hour before
breakfast and/or the evening meal. It is supplied in prefilled injection pens.
• May cause hypoglycemia when administered with a
sulfonylurea but not with metformin.
• When initiating exenatide therapy, the dose of
sulfonylurea should be reduced.
•Not approved for use with nateglinide, repaglinide, or
insulin.
199
Exenatide (Byetta®)
Side Effects
200
Exenatide (Byetta®)
Side Effects
• Not to be used with alpha-glucosidase inhibitors.
• Can delay onset of activity or lower the absorption of
oral drugs (take them one hour before injection).
• Nausea, vomiting, and diarrhea were the most frequent
adverse events.
• Pregnancy category C (evidence of fetal harm in
animals)
201
Liraglutide (Victoza) a New GLP-1
Agonist
202
Liraglutide (Victoza) a New GLP-1 Agonist
• Similar to exenatide, a peptide drug that must
be injected.
• Could be expected to behave very similarly to
exenatide.
• Unlike exenatide (at least to date) liraglutide
caused thyroid tumors in animals.
203
DPP-4 Inhibitors
204
DPP-4 Inhibitors
• Can be taken orally
• DPP-4 is an enzyme that degrades several hormones secreted
by the GI tract, including GLP-1
• These hormones, collectively called incretins, increase insulin
secretion and decrease glucagon secretion in response to
elevations in blood glucose.
• DPP-4 inhibitors would be expected to have similar activity to
exanatide (Byetta). But whereas Byetta must be injected
because it is a protein that would be destroyed in the
digestive tract, DPP-4 inhibitors are small molecules that
remain effective when taken by mouth.
205
DPP-4 Inhibitors
Sitagliptin (Januvia) and Saxagliptin
(Onglyza)
206
DPP-4 Inhibitors
Sitagliptin (Januvia) and Saxagliptin (Onglyza)
• Used in Type 2 DM only (depends on pancreatic insulin
secretion for effect).
• Monotherapy (with diet and exercise)
• Can be combined with metformin, a glitazone or
glimepiride (sitagliptin) or glyburide (saxagliptin).
• When taken alone, will not cause hypoglycemia.
• Sitagliptin - renal excretion of unchanged drug (adjust for
renal impairment)
• Saxagliptin – both hepatic metabolism and renal excretion.
Cytochrome P450 inhibitors slow metabolism (lower dose)
• Once daily dosing
207
Pramlintide (Symlin®)
208
Pramlintide (Symlin®)
•
•
Also approved for type 1 diabetes
Approved for type 2 patients who require insulin with or
without concurrent therapy with a sulfonylurea or metformin
(not a glitazone).
•
Initial dose for type 2 patients is 60 μg to be increased to 120 μg
when nausea subsides.
•
Insulin dose should be cut by half when initiating therapy.
•
After a stable dose of pramlintide (60 or 120 μg) is achieved,
insulin dose should be titrated for optimal blood glucose
control.
•
Other issues with pramlintide are the same as for type 1.
209
Insulin for Type 2 DM
210
Insulin for Type 2 DM
• Can be used alone or in addition to oral agents.
• Use is similar to that for type 1
•Newer evidence suggests that tight control of type 2
may be dangerous because the risk of hypoglycemia
is great and not as beneficial as it is for type 1. Most
clinicians will tolerate somewhat higher blood sugars
in type 2 patients.
211
DKA and HHNC
212
DKA and HHNC
HHNC is more
common in type 2.
DKA is more common
in type 1. In HHNC,
the pathway to ketone
formation is not
activated so there is no
acidosis.
Lehne, 2009, Pharmacology for Nursing Care, 7th
ed., Elsevier, p. 682
213
Diabetic Ketoacidosis
214
Diabetic Ketoacidosis
• Out of control states of diabetes
• DKA
– There is an abundance of glucose but no insulin so
the glucose cannot go into the cells
– The body responds by breaking down triglycerides
into fatty acids and then into ketones
• The formation of ketones creates the ketoacidosis and
gives off the fruity smell
215
HHNC
• HHNC (hyperosmolar, hyperglycemic non-ketotic
coma)
– There is an abundance of glucose but it is not being
used, which leads to the hyperglycemia
• With too much glucose, osmotic diuresis occurs (glucose acts
as a diuretic, like mannitol)
– This leads to a loss of water, dehydration, and hemoconcentration
• In HHNC, a lot of fluid is pulled into the
vasculature and death may occur via cerebral
edema
216
Acute Complications of Diabetes
217
Acute Complications of Diabetes
• Diabetic ketoacidosis (DKA) is more common in type 1
• Hyperglycemic hyperosmolar non-ketotic (HHNC) coma is
more common in type 2.
• Treat both with an intravenous insulin infusion (regular
insulin). Bring the blood sugar down slowly with frequent
bedside blood sugar checks.
• Ketonemia (ketones in the blood) of DKA may resolve more
slowly than the hyperglycemia. If so, give D5W to keep the
sugar up and do something with the ketones?*
• Death may be due to cerebral edema caused by fluid shifts.
• Hypoglycemia may result from too rapid insulin
administration.
218
What is first line treatment for
type 2 diabetes?
219
What is first line treatment for type 2
diabetes?
25%
e
D
ie
t
&
ex
er
ci
s
tid
e
Pr
am
lin
ul
in
In
s
la
ge
nt
s
Oral agents
Insulin
Pramlintide
Diet and exercise
O
ra
1.
2.
3.
4.
25% 25% 25%
220
Pregnancy in Type 2 Diabetics
221
Pregnancy in Type 2 Diabetics
•Most oral diabetes drugs should not be used
in pregnancy (except glyburide) because they
might be teratogenic
•They may be teratogenic.
•They may not control blood glucose well
enough to avoid complications in the infant.
•Glyburide or insulin are the choices for pregnant
type 2 diabetics.
222
Gestational Diabetes
223
Gestational Diabetes
•Gestational diabetes is almost always type 2 diabetes that
develops in a pregnant women because of the hormones
•Hormones of pregnancy synthesized by the placenta
increase insulin resistance.
•If the woman had some degree of baseline insulin
resistance (most likely due to pregnancy), she can be
pushed over into the category of frank diabetes.
224
Gestational Diabetes
Complications
225
Gestational Diabetes
Complications
•The pregnancy and infant are at risk for complications of a
diabetic pregnancy, as mentioned before.
•Organomegaly, macrosomia
•After delivery, the placenta is delivered, insulin resistance
returns to baseline and is again successfully compensated
for by increased insulin secretion.
•The mother is at risk for development of type 2 later in life.
•There is some baseline resistance that could get
worse if she gains weight or as she gets older
226
Gestational Diabetes
Treatment
227
Gestational Diabetes
Treatment
• Gestational diabetics may be successfully treated
with strict diet.
• If not, treat with intensive insulin therapy.
• Recent data confirms that gestational diabetes
should be treated aggressively for good outcome of
the pregnancy.
228