31 - diabetes Flashcards
blood sugar, hypo or hyperglycemia?
nervous, shakey, dizzy, condused, headache, cold clammy, fast heart beat, irritability
hypoglycemia
low blood sugar
below 80mg/dl
blood sugar, hypo or hyperglycemia?
weak, tired, frequent urination, increased thirst, decreased appetite, blurry vision, itchy dry skin, breath smells fruity
hyperglycemia
high blood sugar
above 120mg/dl
blood sugar level chart
fasting - 80-120
just ate 170-200
3 hours after meal 120-140
normal pre-diabetic or diabetic ?
normal
blood sugar level chart
fasting - 101-125
just ate 190-230
3 hours after meal 140-160
normal pre-diabetic or diabetic ?
pre-diabetic
blood sugar level chart
fasting - 126+
just ate 220-300
3 hours after meal 200+
normal pre-diabetic or diabetic ?
diabetic
Hypoglycemia presents an acute problem
_ uses glucose almost exclusively as its source of
chemical energy to supply ATP
Brain
Glc yeilds CO2 and water + ATP
Brain only has a few minutes worth of glucose stored.
Need sufficient glucose in bloodstream
moderate hypoglycemia - brain dysfunction
severe hypoglycemia - death
high levels of blood sugar
(hyperglycemia) is also not good for you
Bottom line: your body goes to great lengths to regulate
_ levels
blood glucose levels
have to be regulated can’t be too high or too low
When fasting, the body maintains glucose
in blood at 70 – 100 mg/dl
When you eat, the level of glucose in your blood _.
This triggers insulin
release from the pancreas. Insulin (acting through its receptor) does some
things that lower blood sugar levels.
when you eat, the level of glc rises
After a meal, 2/3 of the glucose in the blood is removed and stored in the _ and _ as glycogen
Once glycogen stores are filled, glucose is converted to _ in the liver and stored as
triglycerides in fat cells
liver
and skeletal muscle
fatty acids
During times of need, glucose is liberated from glycogen and released from
the _ to the blood in order to keep blood glucose levels appropriate.
Glucose (stored as glycogen) in _ is not released but is used within the
muscle as needed
liver releases Glc when needed
in muscle - not released
The _ is responsible for keeping the blood glucose level
where it needs to be
liver
If blood glucose is high, the liver (and muscle) store it as glycogen
_ = glucose -> glycogen
glycogenesis
If blood glucose is low, the liver releases it from glycogen
_ = glycogen -> glucose
glycogenolysis
If the liver runs out of glycogen but still thinks glucose levels are low, it will make
glucose by a process known as _
gluconeogenesis
glycogenolysis until glycogen stores are depleted then if bloodglc is still low, gluconeogenesis occurs
Hormones produced by the pancreas are entrusted with regulating
blood glucose levels
_ cells - secrete somatostatin
_ cells - secrete glucagon
_ cells - secrete insulin
δ cells: secrete somatostatin
α cells: secrete glucagon
β cells: secrete insulin
islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells
_ and _ are
the principal hormones
regulating blood sugar
levels
Glucagon - alpha cells -
Insulin - beta cells
_ hormone stimulates breakdown of glycogen and raises blood glucose levels
glucagon - alpha cells
raises blood sugar
_ hormone stimulates the formation of glycogen
stimulates glucose uptake from blood
insulin - beta cells - lowers blood sugar
high blood sugar promotes
glucagon or insulin release from pancreas
high blood sugar - promotes insulin release
low blood sugar promotes glucagon release
Glucagon or insulin?
acts through a G protein coupled receptor (coupled to Gαs) to elevate cAMP levels and activate protein kinase A.
glucagon
this initiates a kinase cascade leading to liberation of glucose from glycogen, mainly in liver and skeletal muscle.
Glucagon or insulin?
acts through a tyrosine kinase receptor
insulin
- decreases blood glc levels
- promotes storage of fat
- enhances protein anabolism
3 major effects of insulin
- decreases blood sugar - how?
A rise in blood sugar levels triggers insulin release from β cells. Insulin
mobilizes cells to utilize the glucose and store the glucose.
- decreases blood sugar levels - Stimulate glucose uptake by liver, muscle, adipose,
increases glycogen synthesis,
decreases gluconeogenesis
3 major effects of insulin
Insulin promotes storage of fat - how
Promotes fatty acid and triglyceride synthesis (liver)
Increase fatty acid transport into adipose cells (storage)
Increased conversion to triglycerides (adipose)
Decreases breakdown of triglycerides (adipose)
3 major effects of insulin
enhances protein anabolism - how
Increases amino acid transport into cells
Increases general protein synthesis
Decreases general protein degradation
_ is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. There are three common types.
Diabetes mellitus (DM),
NOT - Diabetes insipidus (DI) is a condition
characterized by large amounts of dilute urine
and increased thirst.
Caused by damage to pituitary gland leading to loss of
antidiuretic hormone (vasopressin) release.
a form of diabetes mellitus in which
not enough insulin is produced.
This results in high blood sugar
levels in the body.
DM TYPE 1
Type 1 diabetes happens when your immune system destroys cells in your pancreas called β cells. They’re the ones that make insulin. Some people get a condition called secondary diabetes. It’s similar to type 1, except the immune system doesn’t destroy your β cells. They’re wiped out by something else, like a disease or an injury to your pancreas
_ a longterm metabolic disorder that is
characterized by high blood sugar,
insulin resistance, and relative lack
of insulin
DM type 2
The causes of type 2 diabetes are not completely understood. Obesity and a sedentary lifestyle clearly play roles. Genetic predisposition factors, only some of which are known, also play a role
a condition in which a woman without diabetes develops high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it does increase the risk of preeclampsia, depression, and requiring a Caesarean section. Babies born to mothers with poorly treated gestational diabetes are at increased risk of being too large, having low blood sugar after birth, and jaundice. If untreated, it can also result in a stillbirth. Long term, children are at higher risk of being overweight and developing type 2 diabetes
Gestational diabetes
_ diabetes usually begins before age 40, although there have been people diagnosed at an older age. In the United States, the peak age at diagnosis is around 14
Type 1
pancreas cannot produce insulin
autoimmune disease that
leads to the destruction of β cells
_ diabetes can be thought of as hyperglycemia*
associated with ‘relative’ insulin deficiency**
* High levels of blood glucose
**Not enough insulin to do the job it needs to do
Type II
Type II diabetes develops over time. Genetics play a role but _ and _ are key contributors. Development of cellular resistance to insulin is a key. This insulin
resistance is part of a series of problems known as metabolic syndrome
genetics - some role
obesity and sedentary lifestyle - main role
metabolic syndrome - insulin resistance, high BP, high triglyceride levels, low HDLs
3 principle targets of insulin
liver
skeletal muscle
adipose
Key tissues less responsive to insulin than they need to be. Less glucose stored and utilized by tissues, more glucose in blood. Metabolic changes to compensate for _
insulin resistance
Changes in signaling events will contribute mightily to insulin resistance
_ is the process of glycogen synthesis, in which
glucose molecules are added to chains of glycogen for storage
Glycogenesis
Liver and skeletal muscle are the primary sites of glycogen storage
what does hexokinase enzyme do
glucose metabolism
converts glucose to Glc-6-P
glycogenesis can occur in
liver, muscle, adipose?
liver and muscle
When blood glucose drops, glycogen in is
broken down and glucose is released to the
bloodstream. This process is called glycogenolysis
liver, muscle, adipose?
liver
skeletal muscle has little glucose 6-phosphatase. It utilizes glucose 6- phosphate but does not export glucose
describes the production of glucose
from pyruvate
liver to convert excess amino acids,
glycerol, and lactate (all through
pyruvate) to glucose
gluconeogenesis
It is not identical to glycolysis running in reverse, but close
More important (in the context of blood sugar control), gluconeogenesis provides a way for the liver to basically convert amino acids (derived from muscle protein) into glucose in times of need
first intermediate of pyruvate is _
oxaloacetate
in mitochondria
In times of crisis in muscle: some protein is degraded to amino acids
Through transamination
reactions, _ aminoacid leaves
the muscle and goes into
the blood stream
alanine which is converted to pyruvate
In the liver, the alanine is converted to pyruvate \+ urea (to get rid of the nitrogen) The pyruvate is converted to glucose (via gluconeogenesis) where it gets sent to the blood stream and used where required.
In essence: proteins are
broken down in muscle in
order to provide glucose
Fatty acids are
metabolized by β
oxidation into _ which is metabolized by the TCA cycle and oxalactetate is the last step and gets converted to pyruvate
Acetyl CoA is metabolized by the TCA cycle
Free fatty acids can be
transported in the blood to
most tissues, where they can
provide energy
exceptions?
Exceptions are
brain (FA’s can’t
cross blood brain
barrier)
and red
blood cells (no
mitochondria)
Much of the metabolism of fatty acids is taking place in the liver during times of need. If the liver is also working to provide blood glucose through gluconeogenesis a problem can arise
The liver will only oxidize the
fatty acid to acetyl CoA and will
convert the acetyl Co A to
_
‘ketone’ bodies. Ketone bodies
are not good (ketoacidosis)
If metabolism through TCA cycle is not possible, acetyl CoA from _ in the liver will be converted to ‘ketone bodies’ (acetone,
acetoacetate, β-hydroxybutyrate)
β
oxidation
In times of crises, oxaloacetate
gets diverted from the TCA
cycle to gluconeogenesis
If the liver needs to make glucose
through gluconeogenesis (body is
hypoglycemic), oxaloacetate can be
depleted
If metabolism through TCA cycle is not possible, acetyl CoA from _ in the liver will be converted to ‘ketone bodies’ (acetone,
acetoacetate, β-hydroxybutyrate)
β
oxidation
In times of crises, oxaloacetate
gets diverted from the TCA
cycle to gluconeogenesis
If the liver needs to make glucose
through gluconeogenesis (body is
hypoglycemic), oxaloacetate can be
depleted
You eat and then store food as glycogen, protein, and fat. Later, blood sugar begins to
drop. Troublesome because the brain is totally dependent on glucose as an energy source.
Body starts by using glycogen stores in liver to crank out glucose to the blood. At some
point fat cells will be liberating fatty acids. This is good news for many tissues but not
brain. fatty acids can not be converted to glucose (no path from acetyl CoA).
Thus, if glucose levels drop in the blood, this must be fixed. Body will start degrading
protein and basically turn amino acids into glucose. β-oxidation of fatty acids will be used
to generate ATP (not in brain). Liver is using fatty acids and also trying to crank out glucose
into the blood via gluconeogenesis. It can deplete itself of _, leaving acetyl
CoA stuck (no TCA cycle). Liver starts cranking out ketone bodies.
oxaloacetate
The liver cranking out ketone bodies is a possibility any time the body is
relying too heavily on β oxidation of fatty acids (Metabolism via the TCA cycle
is insufficient to handle the amount of acetyl Co A being produced). As noted
before, one way for this to happen is when a person becomes hypoglycemic
Normally, high
glucose levels stimulate insulin production and insulin stimulates
glucose uptake and utilization by cells. If insulin fails to be made or
cells fail to respond to insulin,
β oxidation of _ is liable to
increase substantially, even though there is plenty of glucose around.
In this case, excess acetyl CoA can be produced, and formation of
ketone bodies increased. In essence, the liver is fooled to act as if it
needs to make glucose (and consequently ketone bodies) even
though it really doesn’t.
fatty acids
What are the acute complications of diabetes
3 things
- Diabetic ketoacidosis
- Hyperosmolar hyperglycemic state
- Hypoglycemia
Symptoms of _
Hyperglycemia
Ketosis
Metabolic acidosis (drop in pH in blood)
diabetic ketoacidosis (DKA)
Insulin action normally suppresses breakdown of triglycerides to fatty acids (FA’s)
and glycerol in adipose cells. Increase in FA’s leads to production of ketone bodies by the
liver
More common in type one diabetes with poorly managed use of insulin
Tx of diabetic ketoacidosis (DKA)
dilute urine, bed wetting, rapid HR, light headed upon standing
kussmaul breathing - deep and labored
fluids - normal saline before ER hospital
insulin - this will start in the ER– must control electrolyte problems first
more common in type 1
Hyperosmolar hyperglycemic state is a metabolic complication of diabetes mellitus (DM)
characterized by
severe hyper/hypo? glycemia,
extreme _,
- plasma,
altered _.
severe hyperglycemia, extreme dehydration, hyperosmolar plasma, and altered consciousness
It most often occurs in type 2 DM, often in the setting of
physiologic stress.
HHS is diagnosed by severe hyperglycemia and plasma hyperosmolality
and absence of significant ketosis. Treatment is IV saline solution and insulin. Complications
include coma, seizures, and death.
Poor glucose utilization coupled with liver cranking out glucose. Severe
dehydration.
Hyperosmolar hyperglycemic state
complications with DM
Low blood sugar, also known as hypoglycemia, can be a
dangerous condition.
Low blood sugar can happen in people with
diabetes who take medicines that increase insulin levels in the
body. Taking too much medication, skipping meals, eating less
than normal, or exercising more than usual can lead to low blood
sugar for these individuals.
Over medication and/or poor eating.
type 1 or type 2?
Both type one and type two diabetes
Chronic complications of diabetes: The result of _ neuropathies retinopathies nephropathies macrovascular complications ulcers infections GI disturbances
hyperglycemia
vascular system (vessels) affected most
These vascular complications are thought to be principally
mediated through diabetes-induced endothelial cell
dysfunction.
Reactive oxygen species (ROS) are thought to be important
mediators of the damage to the endothelium that results in
endothelial dysfunction.
chronic hyperglycemia is thought to enhance
production of ROS
The_ test measures glycation of hemoglobin (a long lasting
protein in the blood). It provides a window into the average blood
sugar of an individual over a period of months
Why red bloods cells and hemoglobin are good for this?
A1C
red blood cell have a mean t1/2 of 115 days
red blood cell are anucleated and do not synthesize protein.
Thus, the glycation of hemoglobin that is measured
reflects a mean value averaging events over several
months.
good A1c test score?
6 or lower - excellent
7-8 good
9 or more acting suggested
_ Test is the
preferred test for Type 1 and Type 2
diabetes or pre-diabetes.
The Fasting Plasma Glucose
Patient will fast overnight (at least 8 hours) Draw blood in the morning (It is best to have this test done in the morning because afternoon results tend to be lower).
Casual (random) glucose blood test
A couple of hours after a meal, a normal blood glucose level would be no
higher than _
140 mg/dl
healthy adults - Glc levels remain relatively stable - still true even is varied diet, stress, and meals
DM and preDM - glucose levels can vary widely over the course of
the day. This is particularly true if the disease is not well-managed. In these people,
random test results will vary widely. Tests may also be consistently high. A random test is
one performed outside your normal testing schedule. Random testing is an important part
of diabetes management. If random glucose levels are acceptable, the therapeutic strategy
is probably working. Wide swings in levels suggest a need to change the management
plan.
Oral glucose tolerance test
- Draw blood for fasting (baseline) level
- Ingest glucose (75 g).
- Draw blood after 1 and 2 hours.
normal < 6.1 mM (110mg/dL) – 1 hou - less than 10; 180, 2 hours less than 7.8 and 140
preDM - 6.1-7; 110-125, 2 hr - 11.1; 200
DM - >7;125 2hr >11.1; 200
drugs to tx DM
insulin - type 1 pretty much starts and ends here - goal is to manage blood sugar levels to mimic natural physio - type 2 usually don’t start with insulin but eventually have to take it
secretagogues - sulfonylureas standard of care - help Beta cells produce insulin - Must have functional β cells for the drugs to work
Liver cells and pancreatic β cells are designed to be glucose sensors (2 reasons)
Blood glucose levels average around 5 mM
Reason 1. The glucose transporter on liver and β cells (GLUT2) has a Km of 15-20 mM. It will let glucose in
at a rate that is dependent on its concentration in blood.
Reason 2. Liver and β cells have glucokinase. Its Km is 10
mM. This means glucose will be converted at a rate that
is roughly linearly proportional to the blood glucose
level.
_ is present in most cells. Its Km for glucose is
0.2 mM. This means that the glucose inside these cells
will be maximally converted to gluc-6-phosphate across
the whole range of blood glucose levels
Hexokinase
_ makes decisions on what to do metabolically based on
this information.
_ make decisions on whether to secrete insulin based
on this information.
Liver - what to do metabolically
β cells - whether to secrete or nah
Pancreatic β cells have a _ channel that is sensitive to the ratio of [ATP/ADP] inside.
The channel functions when the ratio is _. This keeps the cell hyperpolarized (inside -70
mV relative to the outside). If the ratio [ATP/ADP] is high, the channel is blocked, leading to
depolarization of the cell (inside becomes approximately -40 mV relative to the outside).
potassium
fxns when ratio is low - so hyperpolarizing - no AP
Hexokinase is present in all cells except liver and β
cells. Its Km for glucose is 0.2 mM. Glucokinase is
present in liver and β cells. Its Km is 10 mM.
Liver and β cells will only convert glucose to pyruvate and form ATP when glucose
levels are high enough for glucokinase to work. Thus, they can be glucose sensors.
Glucose levels are linked to the [ATP/ADP] ratio in _
high ratio?
low ratio?
β cells
β cell remains
hyperpolarized when glucose levels are low and becomes partially depolarized when
glucose levels are high.
high ratio - glucose comes in - glycolysis - glucokinase
low ratio - doesn’t work but channel is working
Voltage sensitive Ca++ channels respond to membrane depolarization
Secretagogues
A K+ channel regulates insulin release from β cells by sensing _
ATP/ADP
β cells are metabolically designed to be especially sensitive to glucose levels in the blood and respond by adjusting their ratio of ATP/ADP
ATP/ADP low (fasting), K+ channel open, cell hyperpolarized, L-type
Ca++ channels closed,
insulin secreted or nah .
insulin not secreted
ATP/ADP high (after a meal), K+ channel closed, cell depolarized, Ltype Ca++ channel open,
insulin secreted or nah .
insulin secreted
More rapid onset of action, shorter duration of action
than sulfonylureas. Used before meals. Hypoglycemia a
concern if drug is taken and person doesn’t eat. Add on
drugs.
Meglitinides
Some subtle mechanistic distinctions between sulfonylureas and
meglitinides but both work to promote insulin release by
inhibiting K+ efflux from ATP/ADP regulated K+ channels
Glucagon like peptide 1* (GLP-1) and Glucose dependent insulinotropic polypeptide* (GIP) act at the GLP-1 receptor on β cells and stimulate insulin release. )
Exenatide is a GLP-1 agonist. Sitagliptin inhibits GLP1 and GIP degradation
Incretins
minor add on to standard of care
_ drug for diabetes
increase glucose uptake in skeletal
muscle (diminish insulin resistance)
reduce glucose production in liver
reduce intestinal absorption of glucose
anti-oxidant properties on vascular
endothelial cells
modest weight loss
Biguanide (metformin
usually first line of tx for DM type 2
combo with exercise and weight loss
immediate release
and extended release - for patient with GI probs
_ drug for diabetes
usually 1st medication combo with exercise and diet
improves glycemic control (lowers blood
glucose),
less risk of hypoglycemia than
insulin or secretagogues
metformin (diguanide)
why is metformin so good
does not stimulate _ secretion
many patients loss _
will lower HbA1c by about 1.5%
less risky - no hypoglycemia
insulin sparing - does not stimulate insulin secretion
inhibit mitochondrial glycerol-3-phosphate
dehydrogenase (flavoprotein dehydrogenase), thereby disrupting the
glycerophosphate shuttle
Metformin drug for diabetes
inhibit mitochondrial glycerol-3-phosphate
dehydrogenase (_), thereby disrupting the
glycerophosphate shuttl
The net result of this shuttle is cytosolic NADH is converted to NAD+ and mitochondrial FAD is converted to FADH2. Your body does this as a means to utilize NADH produced by glycolysis to produce ATP through oxidative phosphorylation/electron transport
Inhibiting this process has two
important consequences as it relates
to liver production of glucose.
inhib flavoprotein dehydrogenase
- [NADH/NAD+] increases so less pyruvate
becomes available for gluconeogenesis. - [NADH/NAD+] increases so less
glycerol (from triglyceride breakdown)
goes down the path of gluconeogenesis
(via DHAP).
this inhibits gluconeogenesis by liver
metformin
inhibition of mitochondrial glycerol-3-phosphate
dehydrogenase by metformin inhibits _ by the liver
gluconeogenesis
metformin inhibs gluconeogensis
inhibits the
mitochondrial respiratory
chain complex I
This could increase glucose utilization
through glycolysis
This could also decrease levels of ATP and
increase levels of ADP and AMP. This is very
important because it could activate _
AMP
dependent protein kinase (AMPK)
AMP activated
protein kinase can
sort of be thought of
as the ‘anti-glucagon’
increase glc uptake, glycolysis, fatty acid oxidation,
decrease fatty acid synthesis, sterol syntheis, glycogen synethis, protein synthesis
_ decrease insulin resistance
These drugs are agonists of the peroxisone
proliferator-activated receptor γ. (PPAR-γ)
Thiazolidinediones
These effects by
PPAR-γ agonists
diminish insulin
resistance.
_ is a pathological condition in which cells fail to respond to the normal actions of the hormone insulin
the body produces insulin under conditions of insulin resistance, the cells in the body are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar, this is a compnent of diabetes
_ regulates fatty acid storage and glc metabolism, the genes activated by _ stimulate lipid uptake and adiopgenesis by fat cells
insulin resistance
PPAR-γ agonist - thiazolidinediones
decrease inflammation,
These drugs act by inhibiting the digestion of
glucose
delay digestion and absorption of carbs in GI tract
α-glucosidase inhibitors
this enzyme breaks down starch and disaccharides to glucose - so we inhib it
