2. Learning objectives
By the end of this lecture, students should be able to:
1. Define diabetes
2. Differentiate type 1 diabetes from type 2
3. Explain the pathophysiology of Diabetes
4. Correctly explain the pharmacological action of
insulin and oral hypoglyceamic drugs including their
side effects and contraindications
3. Diabetes Mellitus
Chronic systemic disease characterized by
metabolic and vascular abnormalities
Disorder of carbohydrate metabolism
Results from inadequate production or
underutilization of insulin
4. Diabetes Mellitus
Characterized by glucosuria and hyperglycemia
Two forms—Type 1 and Type 2
Type 1—patient secretes no insulin. Cause is felt to
be autoimmune.
Type 2- patient secretes insufficient amounts of
insulin and insulin receptors are resistant to
existent circulating insulin
5. Diabetes Mellitus
Symptoms: hyperglycemia, glucosuria, polyuria,
polydipsia, polyphagia, and possibly itching.
Fasting blood glucose is higher than 6mmol/l
Manifested by: weight loss, weakness, increased
frequency of infections, poly’s
6. Diabetes Mellitus
Without intervention, significant complications will
ensue.
Include: retinopathies, glaucoma, neuropathies,
cardiovascular disease. PVD. Increased incidence
of toxemia of pregnancy.
7. Pathophysiology
Insulin secreted by beta cells
Insulin binds with and activates 80% of cells
Liver, muscle, and fat cells are primary tissues for
insulin action
With insulin receptor binding, cell membranes
permeable to glucose into the cells
8. Pathophysiology cont.
Increased cell permeability also allows for amino
acids, fatty acids and electrolytes to enter cells
Changes cause anabolism and inhibit catabolism
9. Pathophysiology cont.
Carbohydrate metabolism
Insulin increases glucose transport into liver,
skeletal muscle, adipose tissue, the heart, and even
uterus.
Must be present for muscle and fat tissues to use
glucose for energy
Insulin regulates glucose metabolism to produce
energy for cellular functions
10. Pathophysiology cont.
Fat Metabolism
Insulin promotes glucose into fat cells
where it is broken down
One of breakdown products is A-
glycerophosphate, combines with
fatty acids which ultimately forms
triglycerides
This is the mechanism by which
insulin promotes fat storage
11. Fat Metabolism
When insulin is lacking, fat is released
into the bloodstream as free fatty
acids.
Blood concentrations of triglycerides,
cholesterol and phospholipids are also
increased
12. Protein Metabolism
Insulin increases the total amount of
body protein by increasing transport
of amino acids into cells and
synthesizing protein within the cells
Insulin potentiates the effects of
growth hormone
Lack of insulin causes protein
breakdown into amino acids
13. Endogenous Insulin
Glucose is the major stimulus of
insulin secretion
Oral glucose is more effective than
intravenous glucose because glucose
in digestive tract increases the
release of gastrin, secretin,
chlecystokinin, and gastric inhibitory
peptide
Also stimulates vagal activity
15. Endogenous Insulin
Factors that inhibit insulin secretion
include:
Hypoxia
Hypothermia
Stimulation of alpha adrenergic 2
receptors
16. Classification of Two Types of
Diabetes
Type 1 diabetes results from an
autoimmune disorder that destroys
pancreatic beta cells
Usually has sudden onset
Associated with high incidence of
complications
Requires exogenous insulin
10% of those with diabetes are type I
17. Diabetic Ketoacidosis (DKA)
Life-threatening complication occurs with
insulin deficiency
Glucose cannot be used by body cells for
energy so fat is mobilized for this purpose
Mobilized fat is then extracted by liver and
broken down into glycerol and fatty acids
Fatty acids further broken down into
ketones
18. DKA
Accumulation of ketones results in acidemia
Attempts to buffer acidic H+occurs by ionic
exchange, intracellular potassium exits
cells. H+ ions enter cells. Result is
excretion of potassium in urine.
Kidneys attempt to buffer by excreting
ketones
Pulmonary attempt to buffer by Kussmaul
breathing
19. Clinical S/S of DKA
Kussmaul breathing
Nausea and vomiting
Thirst
Polydipsia, polyphagia and polyuria
Hypotension
Tachycardia
shock
20. Type 2 Diabetes Mellitus
Characterized by hyperglycemia and
insulin resistance
Results from increased production of
glucose by liver and decreased
uptake of glucose in liver, muscle and
fat cells
Insulin resistance—higher than usual
concentrations of insulin are required
21. Type 2 Diabetes Mellitus
Occurs at any age
Gradual onset
Less severe symptoms initially
Easier to control
More MIs and strokes
90% of those with diabetes are Type
2
multifactorial
22. Hyperosmolar hyperglycemia
nonketotic coma (HHNC)
Occurs in Type 2 Diabetes
Because patient has some
endogenous insulin, no ketosis
develops
Blood sugars can be >800-1000
Can result in hypovolemic shock,
renal problems, stroke, coma and
even death
23. Metabolic Syndrome or Syndrome X
Comprised of a set of risk factors
which include:
1. Central abdominal adiposity (men
waist size greater than 40 inches
(101.1 cm), women greater than 35
inches (89 cm)
2. Fasting triglycerides greater > or
equal to 150 mg/dl
3. HDL cholesterol (less than 40 in men,
less than 50 mg/dl in women
24. Metabolic Syndrome cont.
4. Blood pressure greater than or equal
to 130/85
5. Fasting glucose greater than or equal
to 110mg/dL
Also possess prothrombotic and
proinflammatory tendencies
25. Metabolic Syndrome cont.
All factors are interrelated
Obesity and lack of exercise tend to
lead to insulin resistance
Insulin resistance has a negative
effect on lipid production. Increase
VLDL, LDL, TG and decreasing the
HDL.
Insulin resistance leads to increased
insulin and glucose levels in blood.
26. Hypoglycemic Drugs
Insulin lower glucose levels by
increasing glucose uptake by cells
Indicated for Type 1 DM, often in
Type 2 DM, in those with chronic
pancreatitis, in those on TPN, to treat
hyperkalemia (infusion with dextrose
and insulin)
Available insulins are pork and human
27. Age-Related considerations
Type 1 DM in children
Consistent diet, blood glucose
monitoring, insulin injections and
exercise
Blood sugar control essential to
maintain normal growth and
development
Infections and illnesses can cause
wide fluctuations
28. Type 1 DM in children cont.
Children highly susceptible to
dehydration
Rotation of sites is very important
Avoiding hypoglycemia is a major
goal in infants and young children d/t
damaging effects on growth and
development
29. Type 1 DM in children
s/s of hypoglycemia include: hunger,
sweating, tachcardia, irritability and
lethargy.
30. Age related considerations in older
adults
Close monitoring of blood glucose levels
Visual impairment may affect their ability to
self administer medication
May have renal insufficiency so caution
w/certain antidiabetic meds a concern
Caution with metformin if renal impairment
Glitazones can predispose to fluid retention
and heart failure
31. Question time
1. The pathogenesis of hyperglycemia in type 2 diabetes
includes all the following mechanisms ( true or false)
a) Increased glucose production by the liver
b) Impaired insulin secretion
c) Decreased glucose uptake from the skeletal muscle
d) All of the options given are correct
32. 2. Which of the following is the definition for diabetes type 1?
(best option)
a) The immune system destroys beta cells and no more
insulin is being produced
b) The body becomes resistant to insulin
c) Insulin is produced but not efficiently used up
d) Receptors for insulin are destroyed
33. Insulin
Human insulin is chemically identical
to endogenous insulin but it is not
derived from the human pancreas
Cannot be given orally
Insulins differ in onset and duration
of action. Ultra-short, short,
intermediate and long acting.
34. Rapid acting insulin
Insulin lispro (Humalog) or insulin
aspart (Novolog) are very shorting
acting insulins
More effective in decreasing post-
prandial hyperglycemia
Less likely to cause hypoglycemia
before the next meal
Onset is 15’, peaks in 1-3 hours,
duration is 3-5 hours
35. Insulin cont.
Short acting Insulins
1. Regular Iletin II, Humulin R, Novolin
R
2. May be given sub Q or IV
3. May be given as a continuous IV drip
4. The only insulin that may be given IV
5. Onset is ½-1 hour, peak is 2-3 hours
and duration is 5-7 hours
36. Intermediate-acting Insulins
Isophane insulin suspension (NPH,
NPH Iletin II, Humulin N, Novolin N)
Onset is 1-1.5 hours, peaks in 8-12
hours and duration is 18-24
37. Long-acting Insulin
Extended insulin zinc suspension
Onset is 4-8 hours, peaks in 10-30
hours and duration is 36+ hours
39. Insulins cont.
Insulin Analogs
Lispro and aspart as previously
described
Insulin glargine (Lantus)-once daily at
bedtime. Onset is 1.1 hours, peak is
none, duration is 24 hours
Must not be diluted or mixed with
any other insulin or solutions
40. Oral Hypoglycemic Drugs
Five types used to treat Type 2 DM
Sulfonylureas—oldest. Increase
release of insulin. Also decrease
production of glucose in the liver,
increase the number of insulin
receptors and increase peripheral use
of glucose. Effective only if have
functioning beta cells.
Primary side effect is hypoglycemia
41. Sulfonylureas cont.
First generation are essentially
obsolete ( glibenclamide)
Use 2nd generation agents
Are glipizide (Glucotrol), glyburide
(Diabeta)and glimepiride (Amaryl)
Can be used with metformin,
glitazones, insulin or acarbones
Caution w/renal or hepatic
impairment. Not used in pregnancy.
42. Alpha glucosidase Inhibitors
Acarbose (Precose) and miglitol (Glyset)
inhibit alpha-glucosidase enzymes
(maltase, amylase, sucrase) in GI tract.
Delays absorption of complex CHO and
simple sugars
Can be combined therapy w/insulin or
w/sulfonylurea
Contraindicated in cirrhosis, malabsorption,
severe renal impairment
44. Biguanides
Metformin (Glucophage) increases the use
of glucose by muscle and fat cells,
decreases hepatic glucose production, and
decreases intestinal absorption of glucose
Does not cause hypoglycemia
May be used alone or in combination
Contraindicated in liver or renal
impairment. Can result in lactic acidosis.
45. Biguanides cont.
Must check renal function before
beginning this medication
Caution with parenteral radiographic
contrast media containing iodine. May
cause renal failure and has been
associated with lactic acidosis.
46. Glitazones
Pioglitazone (Actos) and rosiglitazone
(Avandia) are also called
thiazolidinediones or TZDs
Are insulin sensitizers
Decrease insulin resistance. Stimulate
receptors on muscle, fat, and liver
cells. Results in increased uptake of
glucose in periphery and decreased
production by the liver.
47. Glitazones
Contraindicated in patients with liver
disease or who have ALT levels > 2.5
of normal
May be used as monotherapy or in
combination with insulin, metformin
(Glucophage) or a sulfonylurea
Caution in patients with heart failure
Ensure baseline LFTs are performed
48. Meglitinides
Nateglinide and repaglinide are
nonsulfonylureas that lower blood sugar by
stimulating pancreatic secretion of insulin
Monotherapy or in combination with
metformin
Should be taken before or up to 30 minutes
before a meal. Dosage and frequency is
flexible depending on food intake.
49. 2. What is the first-line drug for patients with type 2
diabetes and obesity?
a) Acarbose
b) Metformin
c) Sulphonylureas
d) Insulin
50. Herbals and Dietary Supplements
that affect blood glucose levels
Bee pollen, gingko biloba and glucosamine
are thought to increase blood sugars or
may potentially affect beta-cell function and
insulin secretion
Basil and bay leaf may cause hypoglycemia
Chromium may increase production of
insulin receptors and increase insulin
effectiveness
51. DKA
IV fluids to rehydrate
No use of hypotonic solutions at this
time
Potassium supplementation
IV insulin drip with gradual lowering
of blood sugars
Judicious administration of sodium
bicarbonate
52. Diabetic management “pearls”
When mixing insulins, draw up the regular
insulin first
Tid glucose monitoring is highly
recommended
Allow mild hyperglycemia for the patient
undergoing surgery—treat with short acting
insulins
For elective surgery, schedule patient early
in day to avoid prolonged fasting
53. “Pearls”
Use U-100 syringes for U-100 vials
In patients with insulin pumps, use regular
insulin or insulin aspart. Generally will
deliver one unit per hour w/bolus insulin
before meals
Tight glycemic control can reduce the
complications of diabetes.
Use ACE inhibitors to delay nephropathy
Limit dietary intake of protein
54. “Pearls”
Glitazones must suspect r/t
hepatotoxicity
Metformin cautiously with liver and
renal impairment. Concern that with
hepatotoxicity, because risks of lactic
acidosis are increased.
Rotate sites of injection of insulin to
avoid development of lipodystrophy
55. “Pearls”
Absorption of injected insulin in
abdomen is not uniform with
injections in arms or legs
