BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
Date: 1/9/13
Page: 1
Clicker Question: Which of the following is primarily caused by autoimmunity?
1. Primary hyperparathyroidism
2. Secondary hyperparathyroidism
Hypoparathyroidism could be caused by autoimmunity but not hyperparathyroidism
3. Cushing syndrome (4 causes but none are autoimmune)
4. Addison Disease (autoimmune adrenalitis- autoimmune attack of the adrenal cortex)
Objective: Describe the causes, morphology, pathogenesis, and treatment of Type I and Type II
diabetes.
Diabetes Mellitus
- A group of metabolic disorders sharing the common feature of HYPERGLYCEMIA
- Effects 20 million people in the USA
- 7th leading cause of death in the USA
o Rising
- The 2 main types of diabetes have very different origins but similar symptoms
- Type I diabetes
o Insulin deficiency
 Body isn’t producing enough insulin to take up glucose so get excess glucose in
the blood
o Usually found early in life (teens-early adult) because the immune system attacks β cells
right away
o 5-10% of all cases
o Autoimmune form is Type IA (most common Type I)
- Type II diabetes
o Primarily insulin resistance followed by decreased insulin secretion
 Tissues do not respond to insulin produced by the cells
 β cells are in overdrive producing more and more insulin because the glucose
levels are high so they eventually burn out and die
 Patients can become insulin deficient as well later in the disease
o Majority of diabetes cases
o Usually occurs later in life because it is a progressive disease
o Frequent in obese individuals
- Other types of diabetes
o Account for remaining 10% of cases
 Endocrine problems
 Cushing syndrome: hypercorticolism causes hyperglycemia
o 90% are diabetes mellitus (I and II)
Type I Diabetes
- Symptoms
o Usually develops abruptly
o Altered carbohydrate, fat, and protein metabolism because insulin promotes the storage
of all of these
 Glucose metabolism decreases because cells aren’t able to take it up
 Fat and protein metabolism increases because the cells need another energy
source
 Resulting in a depletion of body’s proteins
o
Lack of energy despite healthy appetite (polyphagia)
 Hunger signal isn’t satisfied because the cells can’t take up the glucose
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
Date: 1/9/13
Page: 2
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Taking in a lot more calories but feel fatigued because the muscle has to process
amino acids and fatty acids which takes longer
 No easy glucose store for energy
Weight loss from breaking down the fat and protein
Metabolic acidosis or Ketoacidosis (Increase in the production of keto acids)
 Because we are using fats as an energy source, we get an overproduction of the
acetyl-CoA which doesn’t get utilized
 Acetone and ketone bodies are formed and released into the blood
 Blood pH decreases
 Can smell acetone on a person w/ type I diabetes’ breath because the
acetone gets into the pulmonary circulation and alveoli to be expired
 In response, rapid and deep breathing to low off CO2 (resulting in a decrease of
blood carbonic acid)
 Kidneys decrease bicarbonate excretion
Polyuria (excessive urination)
 How the disease was first diagnosed
Polydipsia (increased thirst)
 Due to getting rid of excessive amounts of fluid
Dehydration if you don’t drink to rehydrate
 Normal glucose levels are around 100
 After a meal, the glucose level may be 200-300
 Kidneys can and process and reabsorb that amount of glucose into the
blood after its filtered
 Elevated blood glucose levels (300-1200 mg/dl) cause osmotic pressure to drive
water out of cells into extracellular fluid
 Greater than 300: kidney fails to absorb the extra glucose so it is excreted
in the urine and is in the blood itself
 Hyperosmolar blood from the elevated glucose so it wants to pull water
out of the cells to help bring the osmolarity down and dilute glucose in
the blood (feel of dehydration)
 Elevated levels of glucose in urine cause osmotic pressure to inhibit water
reabsorption in the renal tubules
 Excess water is excreted
Onset
o Typically diagnosed between ages 12-22
Morphology and Histology
o Early
 Insulitis
 Inflammation of the islets
 Lymphocyte infiltrate into islets
o Later
 Atrophy of the islets and fibrosis
 β cell depletion and replacement by fibrotic tissue
Genetics
o In some cases, there is a hereditary tendency for β cell degeneration
 Something wrong in a gene that the β cells are lost quickly without any other
effect
o 40% concordance in twins: if 1has it then there is a 40% chance that the other does too
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
Date: 1/9/13
Page: 3
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Pathology
o Usually a combination of genetic predisposition and environmental insult that causes type
I diabetes
 Could be genetically predisposed but the right environmental insult never occurs
so you don’t get diabetes
 Could have the right environmental insult but not be genetically predisposed so
diabetes never happens
o Genetic susceptibility
 Presentation of β cell autoantigen
 Immune system attacks the cells
 Lack of insulin secretion by pancreatic β cells (decreased plasma insulin levels)
 Could be a genetic defect in the immune system
causing the attacks of normal β cells
 Could produce a mutant protein on the β cells that the
immune system recognizes as foregin
o Environment
 Chemicals
 Cow’s milk
o 1.5x more likely to get type I diabetes
if you ingested cow’s milk before 4-6
months of age, especially if there is a
family history of type I diabetes
o Bovine protein β-casein may be autoimmune targets
 Similar structure as a protein on the β cells
 Body reacts to β-casein so already have antibodies to the
casein and they start attacking the β cells
 Viral infections (+ Genetic predisposition)
 Molecular mimicry
o If you mount an antibody response against a virus, thevirus may
have antigenic eptopes on it that are very similar to proteins on
the surface of the β cells
o Virus is gone but antigens circulate in blood for a while
o If they encounter the β cell with the antigen similar to the viral
antigen, may attack it as if it were the virus
 Damage to β cells (rare)
o Altering normal structure of β cell protein that makes it look
foreign to our immune system
o Autoimmune disorder
 T-cell mediated attack of β-cells
 B cells produce anti-islet β-cell antibodies (70-80% of patients)
 10% of patients have some other autoimmune disorder
o Predisposition to autoimmune diseases in multiple organ systems
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Normal healthy β cells then necrotic β cells destroyed by the immune system in a type I diabetic
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
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Date: 1/9/13
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β cell depletion over time
o Normal production at birth until a plateau phase is reached
o At some point early in life, the immune system starts
destroyed the β cells
o There is enough there to produce enough insulin so that
there is no effect on the glucose levels at first
Onset of symptoms quick when we can no longer produce enough
insulin to take care of elevated glucose levels
o Destruction is occurring for years but there is enough β
cells present to produce insulin and mask any affect for a
while until reaching a critical point where there isn’t
enough insulin and hyperglycemia sets in and all the
symptoms come at once
Excess ketoacidosis and dehydration can lead to diabetic coma and death
o 2 major acute effects (most life threatening affects are
long-term)
o Insulin deficiency:
 Fats break down from adipose tissue into the
blood
 Not taking up glucose- hunger feeling
 Muscles break down proteins releasing amino
acids into the blood
 Amino acids are taken up by liver
 Elevated amino acids trigger glucagon
release
 Glucagon triggers the liver to break
down glycogen I and stimulate
gluconeogenesis
 Liver is churning out glucose in addition
to the hyperglycemia we already have
from the inability to take up glucose (adding insult to injury)
 Kidney can’t process all the glucose so volume depletion occurs
 Fatty acids can’t be converted enough as an energy source so have a lot of excess
acetyl CoA
 Keto acids are produced and get Ketoacidosis
Treatment
o Diet and exercise
 Exercising skeletal muscle is insulin-independent so they can take up the glucose
and help reduce the blood levels
o Insulin
 Long lasting insulin and regular insulin at meals
 Injection or infusers that can sense glucose levels and automatically secrete
insulin or be set to a time
o Pancreas or β cell transplant
 Bringing in new, healthy β cells that the immune system hopefully doesn’t
recognize
 Will be immunosuppressed from the transplant so immunosuppressents will be
around to help prevent the immune system from attacking the β cells
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
Date: 1/9/13
Page: 5
Type II Diabetes
- Symptoms
o Altered carbohydrate, fat, and protein metabolism
o Glucose metabolism decreases
o Fat and protein metabolism increases
o Early: mild hyperglycemia after carbohydrate meals (elevated insulin)
 β cells are churning out insulin but target cells aren’t responding
o Late: severe hyperglycemia after carbohydrate meals (decreased insulin)
 Once the β cells are dying out
o Polyuria
o Polydipsia
o Polyphagia as the disease progresses
o Absence of ketoacidosis
 Insulin is present so don’t get the breakdown of fat as an energy source until
much later in the disease once the insulin secretion has stopped
o Appear gradually because it is going on over a long period of time
o Most patients are obese (80%)
 Adipocytokine imbalance leads to insulin resistance
 More adipose tissue = more adipocytokines released = stronger effect on
promoting insulin resistance
 Cause, not a symptom
- Onset
o > 40 years of age, usually 50-60 years of age (adult-onset diabetes)
 Seeing earlier onset due to childhood obesity
o Most common form of diabetes mellitus (80-90% of cases)
- Morphology and Histology
o No insulitis (inflammation)
o Focal atrophy especially after the β cells have burned out
o Amyloid deposits
 β cells secrete amylin (in addition to the insulin) so it is being hypersecreted and
deposits in the islets
- Pathology
o Usually combination of genetic and environmental factors triggering the insulin
resistance
o Decreased sensitivity of the tissues to insulin (insulin resistance)
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Genetic
 Decrease in the number or function of insulin receptors
 Insulin receptor utilizes abnormal signaling pathways
Environmental
 Obesity (very likely)
Increased plasma insulin levels
 Due to β-cell hyperplasia
Leads to normal glucose levels
β cells overwork
Inability of insulin to direct the usage of metabolic fuels
 Hyperglycemia
 Can’t handle the elevated levels of glucose
in the blood
 Prolonged stimulation of β cells
 No insulin can be produced
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
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Date: 1/9/13
Page: 6
 Get full-blown diabetes
o Rarely have the β cells stop functioning right off the bat
Genetics
o Multiple gene defects and polymorphisms
 60-80% concordance in twins
o SHIP2 (lipid signaling molecule possibly involved)
 Src-Homology Inositol-Phosphatase-2
 Lipid phosphatase that is a “-“ regulator of insulin sensitivity (increased levels of
the enzyme lead to increased resistance)
 Separate from adipocytokines
Treatment
o Diet and exercise
o Drugs which increase insulin sensitivity by decreasing liver glucose output from the liver
(metformin/glucophage)
o Drugs which induce more insulin release from the β cells (sulfonylureas/glucotrol)
o Drugs that make adipose and skeletal muscle cells less resistant to insulin (more
responsive) (thiazolidinediones/avandia)
o New drugs inhibit incretin degradation (stomach hormones)
o Insulin used in combination w/ other drugs
 Only if β cell production has ceased since too much insulin can cause problems
too
Diabetes
- Prolonged hyperglycemia induces vascular injury leading to:
o Heart attack
o Hypertension
o Stroke
o Kidney disease (nephropathy)
o Retinopathy/blindness
o Glaucoma and cataracts
o Gangrene of limbs
o Peripheral neuropathy
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Due to vascular AGE (advanced glycation
end products) formation and intracellular
conversion of glucose to sorbitol (polyol
pathway) from elevated glucose
o AGE:
 Result of processing of the glucose in an abnormal way causing an increase in
reactive oxygen species being produced
 Can cross link proteins
 Make endothelium more sticky
 When they bind their receptors, trigger inflammatory responses on their target
cells
 Develop atherosclerosis which leads to the cardiovascular issues
 More lipids are present in the blood since we are using them as an energy
source so those lipids are depositing
o Glucose to sorbitol:
 Increases the absorption of water into cells where sorbitol is found like the lens
causing cataracts
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
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Date: 1/9/13
Page: 7
Glycation of trabecular meshwork proteins and crosslinking of AGE blocks the
ability of fluid to flow through the trabecular meshwork causes glaucoma from
pressure build up
Retinopathy (Proliferative or Non-proliferative)
o Increased activity of polyol pathway inside the
vascular endothelium by hyperglycemia leads to
destruction of capillary pericytes inside the retina
o Non-proliferative:
 Hemorrhages (red spots)
 Exudates (white specks)
 Cotton wool spots
 Macular edema as the fluid is leaking out of
these weakened vessels
o Proliferative:
 Neovascularization
 Need to bring more blood to the tissues since it is leaking out so need to
make new blood vessels that grows into the retina
 New vessels are still leaky
 Leaking into the vitreous forms a clot which causes the vitreous to
contract and pull on the retina
o Retinal detachment
VIDEO 1:45:15
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Gangrene of limbs
o Necrosis and ulceration
o Loss of senstation, a sore, massive infection
o Amputation
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Heart attack
o Myocardial infarction
o About half of persons with diabetes mellitus will die from a myocardial infarction as a
consequence of coronary atherosclerosis
 Atherosclerosis, hardening of the arterial walls, glycation end products
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Atherosclerosis
o Prolonged fat metabolism by liver results in elevated blood cholesterol and fatty acid
levels leading to atherosclerosis (AGE and elevated lipids in blood)
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The metabolic abnormalities that characterize diabetes provoke molecular mechanisms that alter
the function and structure of blood vessels
o Combo of hyperglycemia, free FAs, and insulin resistance leads to vasoconstriction,
inflammation, and thrombosis (blood cells are more sticky, the endothelium is damaged,
emboli form)
BHS 116.2- Physiology II
Notetaker: Stephanie Cullen
Date: 1/9/13
Page: 8
Objective: Describe the similarities and differences between the different types of diabetes mellitus.
Type I vs Type II Diabetes
- Symptom-wise can’t tell a difference but there are a number of differences
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Recurrent blurred vision and peripheral neuropathy are seen more commonly in type II probably
because type II develops over time (slower destruction before we recognize it) vs type I abruptly
shows up and can be treated right away.
Clicker Question: Which of the following is NOT common between type I and type II diabetes?
1. Polydipsia
2. Polyuria
3. Hyperglycemia
4. Insulin resistance (only type II)