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102 Cards in this Set

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What is the definition of Diabetes Mellitus?
A group of disorders of glucose homeostasis:
a syndrome characterized by CHRONIC HYPERGLYCEMIA and other disturbances in carb and fat metabolism
What is the hallmark sign of DM?
hyperglycemia
What are the 3 interrelated processes that regulate glucose homeostasis?
1. Glucose production by the liver: gluconeogenesis
2. Glucose storage (liver and skeletal muscle: glycogen and glycogenolysis
3. Glucose uptake by peripheral tissue: insulin mediated
What is the absorptive state?
priority is to decrease plasma glucose (prevent marked elevation).

-Recent meal and BG levels are on the rise
What is the post-absorptive state?
aka: fasting
where you don't have a constant absorption of glucose from the gut.
What is the priority for the body during the post-absorptive state?
To prevent a marked drop in blood glucose leading to hypoglycemic shock
During the absorptive state, what are the final outcomes of glucose in the blood?
1. skeletal muscle: stored or used for energy
2. Liver: stored as glycogen
3. adipose: triglyceride storage.
What occurs in terms of glucose uptake at the tissue level during the post-absorptive state?
The tissues are no longer allow to uptake glucose from blood and thus keeps it in circulation
What must be done in order to keep glucose in the blood during fasting?
Breakdown of glycogen and production of glucose by the liver.
The vast majority of blood glucose replacement during fasting is done by which mechanism?
Glycogenolysis
How does fat help regulate energy during fasting?
Fat gets broken down and is released in the form of free fatty acids. Tissues can use FFAs as an alternate fuel source instead of glucose
What substrates can be converted into glucose?
Amino acids, pyruvate and lactic acid
Describe all the physiological occurrances that take place during the absorptive state.
1. Decrease in gluconeogenesis and glycogenolysis
2. Increase in tissue permeability to glucose
3. increase in glucose storage
4. Limit use of fat as primary energy source/increase fat storage
What physiologic mechanisms take place during the post-absorptive state?
1. Release of glucose from their stores
2. Making new glucose
3. Limit access to glucose to only those tissues that absolutely need it like the CNS
-Use of fat as primary energy source of lipolysis
What are the 2 glucose transporters we are concerned with?
GLUT 1 and 4
What mechanism does glucose enter and exit cells?
Facilitated diffusion (with a transporter)
What are the characteristics of GLUT 1 transporters?
Allow glucose entry into the cell. Present in every cell in your body and is responsible for the basal BF level.

Expression is increased with prolonged fasting and decreased by persistent exposure to excessive glucose
Where are the GLUT 4 transporters found and what are they responsible for?
Found in cardiac, skeletal muscle, and adipose tissue.

THese are not always available, only when insulin acts on the cells and binds to its receptors
What is the name of the signaling pathway responsible for GLUT 4 transporters?
PI-3K
How do the GLUT 4 transporters take in glucose?
In the presence of insulin, the PI-3K pathway signals the GLUT 4 receptors in vesicles to exocytose and become fused with the membrane of the cell. They will remain there for a limited time until they are internalized again
Other than the uptake of glucose, what other effects does insulin have on cells?
1. Cell growth and proliferation through the activation of the MAPK signaling pathway
2. Cell survival/ prolif/ synthesis of lipids, proteins and glycogen (P1-3K
What are the names of the structures of the endocrine pancreas? What cells make up this structure?
Islets of Langerhans. composed of alpha and beta cells.
What are the Islets of langerhans surrounded by?>
exocrine ducts and capillary beds
Beta cells produce?
insulin
Alpha cells produce?
Glucagon
What is THE hormone of the absorptive state?
Insulin
The hormone of the fasting state is?
Glucagon
What triggers the activation of glucagon?
A drop in blood glucose and a drop in insulin
WHat is the function of glucagon?
Turn on glycogenolysis and shuts down glycogenosis. Stimulates fat breakdown
What is the relationship of insulin to glucagon?
antagonistic
WHat are the actions of insulin?
-Decrease in Gluconeogenosis and Glycogenolysis
-Increase in tissue permeability to glucose (esp. skeletal muscle & fat)
-Increase in Glycogen synthesis
- Promotes lipogenesis, inhibits lipolysis
What are the actions of glucagon?
-Release of glucose from their stores (Glycogenolysis)
-Making new glucose (Gluconeogenesis)
-Limiting access to glucose (esp. skeletal muscle & fat)
-Promotes lipolysis, inhibits lipogenesis
With diabetes I, what hormone is out of control?
Glucagon because you have no regulation due to a lack of insulin
WHich type of DM is described predominantly as an autoimmune disorder where beta cells are attacked and destroyed?
Type I
What are the causes of type I DM?
Immune-mediated

Idiopathic
What is Type II DM?
Syndrome of insulin resistance with relative insulin deficiency.

Levels are not high enough to overcome the resistance
What is the disorder solely caused by a genetic defect of Beta cell function?
Maturity-onset diabetes of the young (MODY)
What is MODY?
Maturity onset diabetes of the young.

-caused by several autosomal genes producing defects in insulin production. Tend to act more like Type I DM.
Give some examples of exocrine pancreatic defects that can lead to DM
1. Chronic pancreatitis
2. Pancreatectomy
3. Neoplasia
4. Cystic Fibrosis
What are the common endocrinopathies that can lead to DM? Why?
1. Acromegaly: excess GH can lead to hyperglycemia
2. Cushing Syndrome: excess glucocorticoids raise the blood glucose
3. Hyperthyroidism: raises blood glucose
WHat are the 2 infections linked to DM?
Cytomegalovirus and Coxsackie virus B
Which drugs commonly increase the risk for developing DM?
1. Glucocorticoids
2. Thyroid hormone
3. alpha interferon
4. Beta andrenergic agonist
5. Protease inhibitors
6. Thiazides
What are the 3 genetic syndromes that have been linked with DM?
1. Down Syndrome
2. Turner Syndrome
3. Kleinfelter syndrome
What is the general distinguishing factor between Type I and Type II DM?
Type I has an absolute insulin deficiency.

Type II has a relative insulin deficiency
What is included as part of the "pre-diabetic" conditions?
1. Impaired glucose tolerance (IGT)
2. Impaired fasting glucose (IFG)
What are the screening tools associated with DM?
1. Oral glucose tolerance test
2. Fasting Plasma Glucose (FPG)
Describe the OGTT.
arrive fasting: get a reading. give them a cocktail of glucose. At regular intervals you take more blood glucose measurements. 30 mins, 1 hour, 2 hours and maybe at 3 hours.
Looking for a peak and a rate of decline. In a healthy individual, the plasma glucose will rise to a peak, and then rapidly go down.

-For someone who is prediabetic, the peak will be high and the rate of decline will be slower.
What are the Fasting Plasma glucose levels for a normal person? Pre-diabetes? DM?
Normal: <100
Pre- 100-126
DM >126
What percentage of DM patients have type I?
10%
What type of disorder is DM Type I thought to be?
An autoimmune disorder in which heredity/genetics and environment are thought to play important roles in pathogenesis
What are the 2 major types of Type I that have been identified?
Immune Type I and Idiopathic Type I
If a pt with DM type I has an autoimmunity against the beta cells only, what will be seen during a blood test?
High glucose and High glucagon
When does Type I DM often occur?
Most commonly develops in childhood and becomes manifest at puberty.

-But can develop at any age including adulthood
What characterizes the clinical onset of type I DM? What about the autoimmune attack time frame?
ONset: Abrupt
Autoimmune attack is chronic
How much destruction of Beta cells brings about the classic manifestation of diabetes?
90%
List the mechanisms for Beta cell destruction.
1. T cell-mediated immune attack against poorly defined B cell antigens
2. Cytokine-induced B cell damage (IFN-gamma, TNFalpha, IL-1 unduced apoptosis)
3. Autoantibodies against islets cells or insulin (detected in 70-80% of pts.) Usually accompanied by autoantibodies against b-cell antigens
a susceptibility on the MHC locus has what affects in the body for DM pts?
Presence of certain MHC II alleles

-affects T cell antigen presentation
Describe the non-MHC gene susceptibility associated with DM.
tandem repeat polymorphs of insulin gene

-affects negative selection of insulin-reactive T cells
What infections have been found to increase the likelihood of autoimmune triggering of Type I DM?
Mumps and rubella
The concordance rate of Type 2 for identical twins is ____ to____% and ____ to ____% between first degree relatives.
50-90%; 20-40%
What are the environmental/lifestyle factors that contribute to type 2?
activity level and eating habits
The most powerful risk factor for Type 2 diabetes is_____.
Obesity

specifically a high abdominal adiposity (waist to hip ration of greater than 1)
What are the 2 metabolic defects that are characteristic of type 2 DM?
1. Decreased sensitivity to insulin by peripheral tissue (insulin resistance)
2. B-cell dysfunction manifested as inadequate insulin secretion relative to insulin resistance and hyperglycemia
What typically occurs 10-20 years prior to the clinical manifestation of type 2 DM?
The beginning of insulin resistance
What is unique about the pre-diabetic phase of type 2?
It is completely reversible, sometimes even by 10% reduction of body fat.
List the quantitative and qualitative abnormalities of the insulin signaling pathway that are commonly seen in Type 2.
1. Down-regulation of insulin receptors
2. Decreased insulin receptor-initiated kinase activity
3. Reduced levels of insulin receptor signaling intermediates
4. Impaired docking and fusion of GLUT 4 containing vesicles with the plasma membrane
During the beginning stages of the development of type 2 DM, what actions does the pancreas take to deal with the peripheral insulin resistance?
It causes a hyperinsulinemic state!
-increases the secretion of insulin and can maintain normal glucose levels for years.
What are the manifestations of EARLY B-cell failure?
-Loss of normal pulsatile/oscillating pattern of insulin secretion
-Loss of "rapid phase" of insulin secretion triggered by elevation of plasma glucose
-Eventually secretory defects affect all phases of insulin release, even though some basal secretion persists
List the manifestations of Late B-cell failure.
-Decreased B-cell mass
-islet cell degeneration
-amyloid islet deposition: type of scar tissue
Why is obesity thought to linked to any kind of insulin resistance?
Obesity is a form of hypertorphied adipose tissue, which triggers an inflammatory response and releases cytokines that cause insulin resistance, esp TNF alpha
What % of cells of obese individuals are made up of macrophages? What is the % for normal weight?
50%; 5%
What does the increase of lipolysis due to obesity result in?
Increased circulated FFAs which cause insulin resistance in fat, skeletal muscle and liver cells
T/F: Obesity is only associated with insulin resistance in the presence of DM?
False
What are the Classic Manifestations of DM?
-Hyperglycemia
-Glucosuria
-Polyuria
-Polydipsia
What are the Acute complications of DM?
1. Hypoglycemia
2. Diabetic Ketoacidosis
3. HHNS
Why do individuals with DM often have glucose levels that far exceed the amount of glucose that they ate?
With insulin resistance, the liver believes it is in a fasting state and begins to make new glucose and breakdown glycogen to be put into the blood. 2 sources of increase glucose levels.
What is the most common acute complication that occurs in type 1?
Hypoglycemia
What is the blood glucose range in adults to be in a state of HYPOglycemia?
60-70mg/dm
Why is the target blood glucose level for a person with Type 1 DM often higher than non-DM individuals?
This is done on purpose to buffer the chance of reaching hypoglycemic levels
What hormone is present when insulin is suppressed?
Glucagon
What is the function of glucagon in a fasting state?
To increase the liver production of glucose and minimize tissue uptake of glucose.
What response occurs when blood glucose continues to fall in spite of glucagon presence?
Sympathetic response
What action does the sympathetic nervous system have in the prevention of hypoglycemia?
1. Stimulates the liver to produce more breakdown of glycogen and more gluconeogenesis
2. release catecholamines to stimulate fat breakdown
3. Makes you AWARE of the fact that you need to eat.
What occurs when a DM pt experiences hypoglycemia too regularly? What is this called?
The sympathetic response adapts to the stress and stops responding at the early onset of hypo.

Called hypoglycemia unawareness
What is the first sign for a person with hypoglycemia unawareness that has now become hypoglycemic?
They may pass out. WIll have CNS changes.
which patients often get Diabetic Ketoacidosis?
Type I only
What is diabetic ketoacidosis?
Individuals with absolute insulin deficiency lack the ability to prevent fat metabolism. The fat metabolism causes the production of keto-acids.
When does diabetic ketoacidosis often occur in DM patients?
When type I patients have an infection, trauma, surgery or MI: increased stress
What are the clinical manifestations of diabetic ketoacidosis?
-Kussmaul respirations
-postural dizziness
-CNS depression
-ketonuria
-nausea
-abd pain
-thirst/polyuria
What does adipose tissue due when insulin levels are non-existant?
It is a cue to break down
Why are individuals that have Beta cell autoimmune type 1 at even higher risk for diabetic ketoacidosis?
These individuals have working alpha cells: glucagon.

Glucagon acts to break down fat, which translate into even more keto-acid production
Why are Type 1 patients at risk for a huge BP crash?
The absence of insulin makes the liver feel it is in a fasting state and thus increasing glucose production and glycogenolysis. This causes more glucose in the urine and osmotic diuresis.

-Despite the polydipsia the person will be dehydrated.
Why do Type 2 not get DKA?
Type 2 patients have a small amount of insulin in the body which is enough to suppress fat breakdown.
When is ketoacidosis most often seen in DM patients?
At the time of the first diagnosis
What is the most common complication of DM seen in type 2 patients?
HHNS.
What is HHNS?
A complication of type 2 DM patients that is similar to DKA with no acidosis
What is the leading cause of death of diabetics?
Heart disease
name a macrovascular complication that can occur in DM pt.
Atherosclerosis leading to CAD
What are the 2 most common microvascular diseases that are chronic complications of DM?
1. Diabetic nephropathy
2. Diabetic Retinopathy
Neuropathy in DM pt tends to damage which nerves?
the unmyelinated nerves, which are almost exclusively sensory nerves
Why are DM patients a fall risk?
Autonomic neuropathy can cause damage to the Baroreceptor reflex which allows them to maintain BP from sitting to standing.
Where is sensory neuropathy most commonly found>?
Toes and feet