Insulin and Diabetes Flashcards
What are the 3 cardinal signs that someone might have diabetes?
*Note: these are not diagnostic criteria
-Polydipsia
-Polyuria
-Polyphagia
What is polydipsia?
Extreme/ excessive thirst
What is polyuria?
Excessive urination
What is polyphagia?
A constant feeling of hunger
What causes polydipsia and polyurea in diabetic patients?
High blood glucose levels -> Glucose in urine -> Excessive water loss -> Dehydration/Thirst
What causes polyphagia in diabetic patients?
Inability to utilize glucose as fuel -> Decreased body weight -> Excessive hunger
What is Type 1- Insulin-Dependent Diabetes Mellitus (IDDM)?
An autoimmune response that specifically targets pancreatic beta cells.
This type of diabetes has an early age of onset
What is the role of beta pancreatic cells?
They produce insulin and secrete it when glucose is high
What is the prevalence of Type 1 diabetes in the diabetic population?
10% of diabetic population
What are some markers of Type 1 Diabetes?
-Glucose intolerance
-No functional insulin secretion (near complete loss of pancreatic beta cells)
-Dependency on exogenous insulin
-Tendency toward ketoacidosis
What is the age of onset of Type 1 diabetes?
Early age of onset (mean =12)
What are some possible triggers for Type 1 Diabetes?
-Viruses
-Chemicals
-etc.
(In genetically predisposed individuals)
Do patients with Type 1 Diabetes typically have a family history of the disease?
No
Juvenile Onset Diabetes Mellitus (JODM) is another term for what kind of diabetes?
Type 1 Diabetes
What role does insulin play in ketoacidosis?
Insulin is an inhibitor of ketoacidosis
-As a result, the ability to shut down ketoacidosis is greatly diminished in diabetes patients
What are ICA and IAA?
Two antibodies against antigens that are present in pancreatic beta cells
-Patients with Type 1 diabetes start out negative for these two antibodies, but eventually gain them after precipitating events
-These antibodies mount an autoimmune response and attack insulin-producing pancreatic beta cells
What result would a patient with Type 1 Diabetes get on an oral glucose tolerance test (OGTT)?
The patient would show hyperglycemia after beta cell mass (BCM) decreases enough, because insulin would not be produced enough to clear glucose
Fasting Blood Glucose levels (FBG) are normal until what percent of Beta Cell Mass (BCM) is lost?
70% of BCM
*After this is lost, there is a MASSIVE increase in FBG
What is C-peptide?
A product of insulin processing that acts as a marker for insulin secretion in the presence of exogenous insulin
*If there is any beta cell mass left, then there will be some C peptide left
What are the most common types of autoantigens associated with Type 1 Diabetes?
Secretory granules
-The secretory process is likely what makes these so antigenic since they are exposed to the outside of the cell during insulin secretion
What is IA-2 and what is its relevance to Type 1 diabetes?
IA-1 is a protein present in secretory granules in pancreatic beta cells. It is a common autoantigen found in individuals with Type 1 Diabetes
57% of non-diabetics with antibodies against IA-2 will develop Type 1 Diabetes
99% of Type 1 diabetics have antibodies against IA-2
**This is one of the most prominent markers for diagnosing Type 1 diabetics
What is the result of having antibodies against one or more beta cell proteins?
The patient has an increased risk for developing Type 1 diabetes
What are the two types of Type 2 diabetes?
Non-obese and Obese
What is Type 2 -Non-Insulin Dependent Diabetes Mellitus (NIDDM)
Obese: Cells that respond to insulin become less responsive (resistant) to insulin. This leads to an over secretion of insulin which puts more stress on beta cells and leads to a loss of beta cell mass (BCM)
Non-obese: Patients have mutations in specific proteins that cause insulin secretion in response to glucose to be low. These patients retain some ability to secrete glucose just not at a healthy level. *These gene mutations are often monogenic and can be traced back to a single mutation in a specific gene
What are the percents of incidence in the diabetic population of Type-2 diabetes?
Non-Obese: 10%
Obese: 80%
What is the typical age of onset for Type 2 diabetes?
Non-obese: Under 25 (Maturity Onset Diabetes of the Young) (MODY)
Obese: Over 35 (Adult Onset DM)
Do patients with Type 2 Diabetes typically have a family history of it?
YES
(This is true for both obese and non-obese Type 2 diabetes)
What are the consequences associated with a lack of insulin?
1) Hyperglycemia
2) Glucosuria
3) Hyperlipidemia
4) Uninhibited glucagon
How can a lack of insulin lead to hyperglycemia?
1) There is a decrease in glucose uptake into cells where glucose uptake is insulin-dependent (leaves more glucose in the extracellular space)
2) There is decreased glycogen synthesis (less glucose is taken up and stored)
*This process is stimulated by insulin
3) There is an increased conversion of amino acids to glucose (Gluconeogenesis)
*This process is normally inhibited by insulin
How can a lack of insulin lead to glucosuria?
A lack of insulin leads to hyperglycemia and resulting high blood sugar
-This leads glucose to get into the urine which causes more water to be lost by osmosis
How can a lack of insulin lead to hyperlipidemia?
There is increased fatty acid mobilization from fat cells and increased fatty acid oxidation
-This leads to an accumulation of byproducts (ketone bodies) and ketoacidosis
How can a lack of insulin lead to uninhibited glucagon?
Glucagon secreting cells become resistant to insulin
-As a result, there are increased glucagon levels present at the same time that there is increased blood glucose levels
-Glucagon stimulates the release of even more glucose from the liver and this ultimately can lead to hyperglycemia
What are the complications associated with a lack of insulin?
1) Cardiovascular
-Micro and macro angiopathies, compromised
blood flow, damaged blood vessels
2) Neuropathy (nerves)
-Increased blood glucose levels leads to increased utilization of the polyol pathway which converts glucose to sorbitol to fructose (especially the glucose to sorbitol pathway done by aldose reductase)
-Water accumulation in neurons leads to reduced protection from oxidative damage
3) Nephropathy (renal)
-Renal vascular changes
-Changes in the glomerular basement membrane
4) Ocular
-Cataracts
-Retinal microaneurysms
-Hemorrhage
5) Increased susceptibility to infections
What blood glucose level indicates hypoglycemia?
< 70
What is the major adverse affect associated with a high A1C level?
Retinopathy
(occurs at A1C of 6 or greater)
What is A1C?
A measure of how much glucose is hanging onto hemoglobin in red blood cells
**Way to measure what the average blood glucose level has been over an extended period of time
(measures the percentage of red blood cells that have glucose-coated hemoglobin)
Why is glucose so toxic? (Especially during hyperglycemia)
The structure of glucose is an aldehyde which is a very reactive molecule
-Glucose can react and oxidize with other molecules to create even more reactive molecules as well
-Oxidation products of glucose react irreversibly with proteins to form Advanced Glycation End-Products (AGE’s)
What are Advanced Glycation End-products (AGE’s)?
Oxidation products of glucose react irreversibly with proteins to form Advanced Glycation End-Products (AGE’s)
AGE’s bind to the RAGE receptor
AGE’s can cause:
-Loss of normal protein function
-Acceleration of the aging process
***THEORIZED TO ACCOUNT FOR MANY OF THE LONG-TERM COMPLICATIONS OF DIABETES
What is the role of the RAGE receptor?
-Present mainly on leukocytes and endothelial cells
-Part of the major histocompatibility (MHC) complex
Regulates inflammation
What is the role of carboxymethyl lysine (CML) and carboxyethyl lysine (CEL)?
When glucose reacts with proteins during, they can be degraded into peptides containing CML and CEL
-These peptides bind to and activate RAGE receptors which promotes inflammation
-Chronic inflammation can occur in patients with diabetes if RAGE receptors are being constantly activated due to hyperglycemia
How can the initiation of the Polyol pathway during hyperglycemia lead to cell damage?
The polyol pathway is the pathway by which nerves process glucose for storage since they do not make glycogen
Glucose is reduced to sorbitol by Aldose reductase and then converted to fructose which is stored in the nerves
2 ways overuse of this pathway can lead to cell damage:
1) Accumulation of alcohol glucose (sorbitol) causes osmotic swelling of neurons which can lead to neuropathies
2) This pathway consumes a large amount of NADPH which makes the neuron more susceptible to oxidative damage
How can the initiation of the Hexosamine pathway during hyperglycemia lead to cell damage?
Fructose-6-P accumulates and initiates the pathway
-UDP-GlcNAc is created and it acts as a substrate for o-glycotransferases that put NAc onto hydroxyl groups of proteins . This can change their function.
There are 2 important transcription factors in response to glucose metabolism that can get NAc transferred to them which modifies their function
What is the role of alpha subunits on the insulin receptor?
-Regulatory unit of the receptor
-Represses catalytic activity of beta subunit
*Repression is relieved by insulin binding
What is the role of beta subunits on the insulin receptor?
-Contains the tyrosine kinase catalytic domains
-Conducts autophosphorylation!!
What is the structure of the insulin receptor?
A pre-formed dimer through disulfide cross-links
(dimer of dimers)
How many molecules of insulin are required to activate the insulin receptor and what is the result of insulin binding?
1 molecule of insulin
-Repression of the beta subunits by alpha subunits is relieved by the binding of insulin
-This leads to autophosphorylation
What is the result of activation of the insulin membrane receptor by insulin?
Increased Lipogenesis
Increased Glycolysis
Increased Glycogen synthesis
Decreased Gluconeogenesis
Cell growth + proliferation
Increased DNA+RNA synthesis
Is insulin catabolic or anabolic?
Anabolic
-Allows cells to use nutrients, grow, and proliferate
What is the effect of insulin on the liver?
Inhibits:
-Glycogenolysis
-Ketogenesis
-Gluconeogenesis
Stimulates:
-Glycogen Synthesis
-Triglyceride Synthesis
What is the effect of insulin on the skeletal muscle?
Stimulates:
-Glucose transport
-Amino Acid Transport
(used for nutrition/ anabolic effects)
What is the effect of insulin on adipose tissue?
Stimulates:
-Triglyceride storage
-Glucose transport
What happens with glucose disposal during periods of fasting?
The majority of glucose disposal is non-insulin dependent (liver, GI, brain)
Some glucose disposal is insulin-dependent in the skeletal muscle
*Glucagon is secreted to prevent hypoglycemia
What happens with glucose disposal during fed periods?
The majority of glucose disposal is insulin-dependent in the skeletal muscle
A little bit of glucose disposal occurs in the adipose tissue (insulin-dependent)
*Glucagon secretion is inhibited
*Free fatty acid release from adipose tissue is inhibited by glucose
What is the result of having decreased serum free fatty acids (FFA)?
-Enhances insulin action on skeletal muscle
-Reduces glucose production
Where are the 4 glucose transporters found?
GLUT 1 - Widely expressed, beta cells?
GLUT 2 - Beta cells, liver
GLUT 3 - Neurons
GLUT 4 - Skeletal muscle, Adipocytes
Which glucose transporter is insulin-induced?
GLUT 4
What hormone do A cells secrete in the pancreas?
Glucagon
What hormone do D cells secrete in the pancreas?
Somatostatin
What hormones do B cells secrete in the pancreas?
Insulin, Amylin
What is the role of the pancreas in terms of insulin?
Site of insulin production and secretion
What is the job of glucagon?
-Stimulates glycogen breakdown
-Increases blood glucose
What is the job of somatostatin?
-Inhibits secretion
-Has a local affect
What is the job of insulin?
-Stimulates uptake and utilization of glucose
What is the job of amylin?
Co-secreted with insulin
-Slows gastric emptying
-Decreases food intake
-Inhibits glucagon secretion
How is insulin synthesized in the beta cells?
-Synthesized as a single peptide
-Deposited in secretory granules
-Processed in secretory granule by proconvertase
-Processed from the pro-hormone: Proinsulin
-Proconvertases cleave the A and B chains, and the C connecting peptide
-A and B chain make up the insulin
-C peptide is released in a 1:1 ration with the insulin
What can C peptide tell us about insulin production?
C peptide production is a measure of how well beta cells are functioning to secrete insulin
*C peptides are released in a 1:1 ration with insulin
What is the result of having deleted zinc transporters in insulin granules?
Glucose intolerance
*Zinc condenses insulin into a dense core, when zinc is missing so is this core
What are 3 possible causes of Insulin Resistance?
-Polymorphisms in insulin signaling pathway proteins (rare, inherited mutations)
-Obesity (especially with abdominal fat accumulation) *increased free fatty acid (FFA) levels
-Inactivity
What is the role of the liver?
Outputs glucose
(through glycogenolysis and gluconeogenesis)
What do increased free fatty acid levels associated with obesity predominantly affect?
Insulin-stimulated glucose transport
What 3 things that are increased in obesity can lead to insulin resistance?
-Excess nutrients
-Increased cytokines
-Increased TNFa
In a non-obese person, what affect do resident macrophages have on insulin sensitivity?
Increase sensitivity by secreting IL-10
In the obese state, what happens when macrophages are infiltrated?
Increased TNFa, IL-6, and MCP-1 secretion
*leads to insulin resistance
