T1DM affects about ______% or all DM patients
T2DM affects about ______% of all DM patients
What happens to roughly 40-60% of gestational diabetes patients
within 15 years
It is projected that 40% of Americans born between 2000-2011 will
develop T2DM which is ___ times the risk for those born 10 years earlier
Life expectancy is reduced by about ____% in diabetics
Patients with T1DM tend to die of _______________ while T2DM patients
die most frequently from _____________
kidney failure, CVD
What is considered "normal" fasting blood glucose?
What is considered "diabetic" fasting blood glucose?
What is considered "normal" non-fasting blood glucose?
What is considered "diabetic" non-fasting blood glucose?
In addition to blood glucose, what diagnostic criteria can be used to
Normal HbA1C is considered < ___%
A ___________ test is one in which a patient must consume a glucose
drink and have their blood plasma levels monitored for a period of 2 hours.
Fasting Oral Glucose Tolerance Test (OGTT)
If plasma glucose exceeds ______ mg/dL at any point during the 2
hours OGTT a diagnosis of DM can be made
Impaired glucose tolerance during an OGTT is considered between ____
What are the 3 classic signs/symptoms of DM:
polyuria, polydipsia, polyphagia
Sudden changes in _________ and ___________ can also be
signs/symptoms of DM
What DM signs/symptoms are more common in T2 patients? What about
acanthosis nigricans, pruritis, impotence
Why is dizziness a symptom of DM?
frequent urination causes hypovolemia which leads to low BP
T1DM was formerly known as _______ diabetes. It can be diagnosed as
late as ____ but peak onset is between:
juvenile, 30, 11-13
T1DM results from the destruction of
pancreatic beta cells
Are T1DM patients usually obese?
T1DM is more common in what ethnicity?
What are the 2 forms (causes) of T1DM?
Is there a strong genetic component to T1DM?
not necessarily, the risk to an identical twin is about 33% which
makes it a weaker link that previously thought
Destruction of pancreatic beta cells leading to DM without the
presence of antibodies (ex. pancreatitis) is known as
Lack of insulin in T1DM shifts the balance to ______-mediated functions:
Glucagon excess leads to decreased glucose uptake by
Why does insulin deficiency and glucagon excess lead to increased
protein catabolism and lipolysis?
body thinks its starving
In the fasting state, glucagon dominates leading to an increase in
what 3 functions?
gluconeogenesis, glycogenolysis, ketogenesis
What causes diabetic ketoacidosis? What does this do to the blood?
What is a sign of this condition?
lipolysis which leads to conversion of acetyl CoA into ketones,
acidifies blood, fruity smelling breath
Pramlintide (Symlin) is a synthetic injectable _________ peptide.
Where is this naturally produced in the body?
amylin, pancreatic beta cells
Pamlintide decreases postprandial glucose levels by slowing _________________
Used as an adjunct therapy in T1DM patients in addition to insulin to
promote satiety after a meal and decrease weight gain
Genetic susceptibility coupled with ________ can lead to insulin
resistance and eventually ________ failure and __________ complications
obesity, beta cell, vascular
Unlike T1DM which is more common in whites, T2DM has a much higher
incidence in what ethnicities?
black, hispanic, native american
List 7 risk factors for T2DM
familial history, BMI >27, sedentary lifestyle, race/ethnicity,
previous impaired glucose test, history of gestational diabetes, PCOS
List 4 treatment strategies for T2DM
exercise/weight loss, oral drug therapy, insulin, treatment of
What are 4 comorbid diseases to T2DM?
dyslipidemias, hypertension, pain, and kidney impairment
___% of T2DM patients are obese, hypertension prevalence is ___ times
higher, and almost all have __________
80, 2x, dyslipidemias
__________ is the most recognizable sulfonurea which is categorized
as an insulin __________
What is required of patients in order to have success with Glipizide?
good pancreatic function
What is an unintended consequence of treatment with Glipizide and why?
hypoglycemia, bc it causes insulin secretion regardless of plasma
What is the brand name for glucophage? What is its effect on the body?
Metformin, reduces gluconeogenesis in liver, and sensitizes the body
to the effects of insulin (specifically post-prandial)
GLP-1 analogs and DPP-IV inhibitors such as Exenatide (Byetta) and
Sitagliptin (Januvia) help increase insulin secretion by enhancing the
function of ________. When do these agents work best? What is a
benefit to this therapy over other therapies?
incretins, increase insulin secretion only when glucose levels are
high, less risk of hypoglycemia
Invokana is a type of _________ inhibitor. What does it do and how
would that lead to an increased risk of UTI's?
SGLT-2, increases excretion of glucose in urine, sugar in urinary
tract is food for bacteria
Hypoglycemia has impacts on the sympathetic nervous system as well as
the CNS. List a few
tremors, palpitations, sweating, confusion, dizziness, fatigue
What is the treatment for diabetic ketoacidosis?
IV insulin and fluid
GLUT 4 receptors are expressed in which tissues?
skeletal muscle, adipose
What is the difference between glycolysis and glycogenolysis?
glycolysis is the breakdown of glucose (6 C) to Pyruvate (3C)
glycogenolysis is the breakdown of glycogen (starch) into glucose
The anabolic production of glycogen from glucose is called
What enzyme converts Glucose-6-Phosphate into glucose?
The pancreas has mixed function which means that it has both
_________ and ________ functions
endocrine and exocrine
Pancreatic islets of _____________ comprise the endocrine pancreas
which are only around ___ % of total pancreatic cell mass, 75% of
which is comprised by what cell type?
Langerhans, 2, beta
What two hormones are produced by pancreatic beta cells?
What hormone is produced by pancreatic alpha cells?
What hormone is produced by pancreatic delta cells?
Active insulin is comprised of 2 subunits linked together by
Proinsulin contains an additional __ peptide that is cleaved off to
form insulin. This peptide is a good marker for ________ function
How can C peptide be used diagnostically?
C peptide should be at a 1:1 stoichiometric ration with insulin in
the bloodstream. If no C peptide is present, it's because insulin is
not being produced. This is most common in T1DM patients
_________ is the hormone of the fed state, while __________ is the
hormone of the fasting state
Insulin's primary functions are (anabolic/catabolic)
What are the 3 tissues primarily affected by insulin?
skeletal muscle, fat, liver
What is one catabolic function of insulin?
Does insulin cause an overall increase or reduction in plasma glucose?
reduction bc it moves it into the cells
Insulin causes K+ to enter cells, lowering extracellular levels. What
could this be used to treat?
Insulin binds to what kind of receptors?
tyrosine kinase inhibitors
Binding of insulin to its ligand receptor causes _____________ of
tyrosine residues within the intracellular domain of the receptor
IRS stands for _______________ and initiates second messenger
pathways that alter _________ synthesis via the regulation of gene transcription
insulin-receptor substrates, protein
The binding of insulin to its receptors causes changes to the second
messenger pathways which lead to a change in membrane ________
activity causing an increase in glucose uptake
What is a major difference in GLUT 2 and GLUT 4 transporters?
GLUT 2 do not translocate, GLUT 2 allows glucose to move in both directions
Glucose moving into a cell is an example of what kind of diffusion?
Glucose gets brought into the cell and phosphorylated into G6P by
hexokinase (aka glucokinase)
How does insulin indirectly promotes glucose uptake by keeping
intracellular concentrations low by
promoting glycolysis and glycogenesis
plasma glucose >100 and an increase in plasma amino acid
secretion, incretins GLP-1 and GIP, PNS function through ACh acting on
M3 receptors are all factors that increase
Somatostatin and sympathetic ____ receptors in the PNS decrease
These cells "monitor" plasma glucose levels and
synthesize/secrete insulin as needed
The main stimulus for insulin secretion is the plasma glucose. High
glucose causes glucose to travel down the concentration gradient
through GLUT2 by facilitated diffusion into beta cells where it is
rapidly phosphorylated and sent into glycolysis and the citric acid
cycle to be converted to ____. Elevation of these levels causes K+
channels to ______, depolarizing the cells and allowing ____ to enter
and function as an intracellular signal for exocytosis and insulin secretion
ATP, close, Ca++
Are GLUT 2 transporters insulin sensitive? Where are they located?
Is hexokinase (glucokinase) insulin sensitive?
What are 3 counter-regulatory hormones to control blood sugar? What
do they work to prevent?
cortisol, glucagon, and Epi; hypoglycemia
What is the major cause of hypoglycemia?
too much insulin
Linear peptide secreted by pancreatic alpha cells
Where are glucagon receptors primarily expressed and to what does it bind?
When coupled to its receptor, glucagon causes an increase in _______
in liver cells
Is glucagon secretion tied to meals?
no, it's fairly constant
Glucagon is the primary hormone of the _______ state
This hormone's main functions are catabolic
Which hormone is primarily anabolic?
Glucagon increases glucose output through what two processes?
Lipolysis releases an abundance of __________ which is then used to
Acetyl CoA, ketone bodies
In fat, glucagon plays a minor role in the elevation of cAMP which
leads to what process?
In pancreatic beta cells, glucagon can elevate cAMP which results in
an increase of insulin. What is this called?
When blood glucose levels fall, the seesaw is tipped in the favor
glucagon which causes what 3 processes to prevail?
glycogenolysis, gluconeogenesis, ketogenesis
What are the only two forms of energy the brain can use?
glucose and ketone bodies
What are 4 factors that inhibit glucagon secretion?
blood glucose >100, somatostatin (inhibits insulin as well),
insulin, GLP-1 (which increases insulin to offset glucagon)
GLP-1 stands for
glucagon-like peptide 1
GIP stands for
gastric inhibitory polypeptide OR glucose-dependent insulinotropic polypeptide
GLP-1 and GIP are
Incretins are intestinal hormones that regulate
Nutrient-sensing cells in intestine secrete incretins in response to
nutrients in gut
Do incretins circulate through bloodstream to activate pancreatic
Are GLP-1 and GIP coded by the same gene?
GLP-1 is a peptide that is synthesized from _________. How is this
precursor differentiated into the two different substances?
proglucagon, posttranslational processing by either intestinal cells
or pancreatic alpha cells
Which incretin accounts for 80% of post-prandial effects?
Both incretins activate GPCRs coupled to Gs which raise cAMP in
Both GLP-1 and GIP are inactivated by and enzyme known as
DPP-IV inhibitors are a new treatment for what disease state?
The effect of this drug class is to help increase glucose-stimulated
insulin secretion from beta cells
Somatostatin was named for its ability to inhibit
This hormone is secreted by the hypothalamus and pancreatic delta cells
List 4 hormones somatostatin works to inhibit:
insulin, glucagon, GH, TSH
Somatostatin serves as a _________ factor in that it acts locally on
nearby ____ and _____ cells
alpha and beta
What condition might a somatostatin analog be useful in treatment for?
acromegaly (gigantism) and GI tumors
Amylin is a ________ secreted by beta cells along with insulin.
Although its role is not completely defined, it's known functions
include decreasing _________ levels of glucose by slowing gastric
emptying and promoting __________. What positive outcome might this promote?
peptide, postprandial, decrease weight gain
During lipolysis, FFA and glycerol are released into the blood. Where
do they go?
FFAs are taken up by tissues for E production and glyercol goes to
the liver to be converted to glucose via gluconeogenesis
Production of Acetyl CoA from FA oxidation in the liver is
(faster/slower) than the TCA capacity to metabolize it. What does this cause?
faster, causes an excess of ketone bodies to diffuse into circulation
Central obesity, hypertriglyceridemia, low HDL, hyperglycemia, and
hypertension are all features of what disease state?
Metabolic syndrome causes in increase in FFA to be released from
expanded adipose tissue which are sent to the liver to be packed into
_____. FFA's reduce insulin sensitivity in muscle by inhibiting
insulin-mediated glucose uptake which depletes _________ stores and
causes ________ accumulation in muscles
VLDL, glycogen, lipid (fat)
Increased circulating FFA from abundant adipose tissues and glucose
from depletion of glycogen stores increases insulin secretion
resulting in a state of _____________. This state may cause enhanced
sodium reabsorption and increase sympathetic activity and drive up _____
hyperinsulinemia, blood pressure
Increased tissue mass in metabolic syndrome can lead to the secretion
of inflammatory mediators leading to increased insulin resistance,
hepatic gluconeogenesis, and lipolysis releasing more FFAs. _________
and FFAs also increase hepatic production of fibrinogen and adipocyte
production of plaminogen activator inhibitor 1 (PAI-1) resulting in a
Reduced production of the anti-inflammatory and insulin-sensitizing
cytokine ___________ is also associated with metabolic syndrome
What apolipoprotein do VLDL have?
Because of their poor solubility, lipids must be packaged within ___________
LPs are macromolecular aggregates that transport ____ and ___________
in the blood. They are characterized as amphipathic because they have
a __________ core and a monolayer of polar amphipathic lipids and
proteins on their surface
TGs and cholesterol, hydrophobic
LPs are differentiated according to size, density, and _________ content
As LPs increase in density they decrease in _____
Which are the largest and least dense LPs with the highest lipid content
Low levels of HDL predispose patients to __________ disease
What determines the metabolic fate of LP's?
its apolipoprotein composition
What LPs participate in the delivery of TGs to fat and muscle?
What LPs are involved in cholesterol transport?
HDL, LDL, and remnants of ApoB-containing LPs
Where is ApoB mainly transcribed?
gut (intestine and liver)
ApoB mRNA is edited differently in enterocytes and results in a
shorter version called _____. Why? No editing occurs in the liver
which results in _____
ApoB-48, presence of enzyme APOBEC-1, ApoB-100
Chylomicrons from the intestine contain ApoB___ while VLDL particles
produced by the liver contain ApoB___
ApoB is synthesized (intermittently/constantly) which allows for
immediate production of chylomicrons and VLDL particles upon ___ availability
ApoB protein is synthesized by ___________ and crosses into the ER
Inside the ER, TG molecules are added co-translationally to the
elongating ______ protein
Addition of lipid molecules to ApoB is known as ___________ and is
mediated by the action of a cofactor protein called _______
ApoB lipidation, microsomal triglyceride transfer protein (MTP)
Newly formed or nascent LP is enlarged in what organelle as
cholesterol and TGs are added to the core?
The ___________ pathway of LP metabolism is centered around dietary
lipids, primarily chylomicrons
The ____________ pathway of LP is primarily made up of VLDL which
resembles chylomicrons but differs in _________.
endogenous, ApoB protein (has 100 rather than 48)
______ particles have higher ratio of cholesterol to TG
Because TGs are hydrophobic, they must be _____________ to be absorbed
Hydrolysis of TGs is initiated in the mouth and stomach by
lingual and gastric lipases
________ lipase is secreted into the small intestine to hydrolyze lipids
Pancreatic lipase inhibitors work by:
What is an unintended consequence of these drugs?
preventing emulsification of lipids meaning they cannot be absorbed,
Biliary lipids and cholesterol are secreted with bile acid in order
to emulsify lipids into _________ for uptake into the cells
Micelles have a _________ head and ___________ tails and are soluble because:
hydrophilic head, hydrophobic tails, they are extremely small
Bile salts remain in the gut and are absorbed from the ileum into the ________________
________________ are drugs used to treat dyslipidemias that bind to
negatively charged bile acids in the intestine to form insoluble
non-absorbable complexes which are then excreted
bile acid sequestrants
Bile acid sequestrants promote the excretion of bile acids along with
lipids. The precursor for bile acids is cholesterol so what effects
might these drugs have on the body?
drive up cholesterol synthesis and increase the conversion of
cholesterol into bile salts making hepatocyte cholesterol
concentrations go down
As a consequence of bile acid sequestrants, will uptake of
cholesterol into the cell increase or decrease? What effect will this
have on plasma cholesterol levels?
The re-esterification of long chain FAs and monoglycerides is done by
the enzyme ____________. What happens to medium chain FAs?
DGAT (diacyleglycerol acyltransferase), absorbed directly into the
hepatic portal system and metabolized by the liver
What does the Niemann Pick C1-Like Protein (NPC1L1) do?
protein channel that takes up cholesterol into the enterocyte, some
of which is pumped directly back into the lumen, the rest of which is
esterified by ACAT
What drug works on NPC1L1?
Ezetimibe inhibits NCP1L1 so it results in a __________ in delivery
of cholesterol to liver, causing hepatic stores to be __________.
First compound approved for lowering total and LDL-cholesterol levels
VLDL assembly increasing in response to increasing flux of FFAs to
liver during _______, and from ____________ from diet
fasting, saturated fats and carbs
In the endogenous pathway, MTP in hepatocytes lipidates ApoB-100 to form
nascent VLDL particles
____ promotes the enlargement of VLDL particles with more TGs
VLDL particles may also acquire additional apolipoproteins such as:
Sometimes these proteins are acquired from _____
apoC1, apoC2, apoC3, ApoE, HDL
Which LPs are primarily TGs and which are primarily cholesterol?
Chylomicrons and VLDL must be activated by ______ in order to be delivered
_____ is a lipolytic enzyme located in muscle and fat
LPL (lipoprotein lipase)
LPL (lipoprotein lipase) binds to ______; TGs become hydrolyzed into
FFAs and glycerol for uptake into cells
LPL is regulated by fed/fasting state. During fasting, FFAs are sent
to _____, during fed state FFAs are sent to _______.
ApoC3 is an LPL inhibitor which allows it to control the rate of
lipolysis of CMs and VLDL keeping TG-rich particles in circulation?
How might a drug therapy capitalize on this?
target and inhibit ApoC3 to reduce blood TGs
After LPL, CMs and VLDL become TG depleted. At what point do these
particles lose their affinity for LPL and dissociate?
50% TG removal
Once TGs have been depleted from CMs and VLDL, ApoA1 and C2 are then
transferred to HDL in exchange for
Once CMs and VLDL receive ApoE from HDL, they are considered
50% of VLDL and 100% of CM remnants are cleared through
receptor-mediated particle uptake
The 4 pathways for receptor-mediated clearance of VLDL and CM
remnants are by. Why are some of these redundant?
LDL-receptors, LDL receptor related protein (LRP), Heparan sulfate
proteoglycan (HSPG), combined activities of LRP and HSPG, redundancies
allow for efficient particle clearance
The 50% of VLDL remnants that don't get cleared through
receptor-mediated uptake are converted to ____ by hepatic lipase
Hepatic lipase further hydrolyzes TGs in the core of IDL so that the
remaining particles are poor in ____ and rich in ______. Further
reduction in size leads to a transfer of ApoE back to ____. What is
the end result?
TGs, cholesterol, HDL, LDL with only ApoB-100
Why does LDL circulate in the blood for so long and account for
65-75% of total plasma cholesterol?
they don't have ApoE which makes them weak ligands for binding to
their only receptor
LDL receptors are expressed primarily in what cells? They are also
expressed in macrophages, lymphocytes, adrenocortical and gonadal
cells. Why gonadal cells?
hepatocytes, gonadal cells produce steroid sex hormones
LDL binds to LDLRs and is taken into cells via
receptor mediated endocytosis
Following endocytosis, LDL is hydrolyzed by lysosomes to release
unesterified cholesterol which affect 3 major pathways:
de novo synthesis, cholesterol esterification (storage), and
downregulation of LDLR receptor expression (feedback control to
decrease further uptake)
High intracellular cholesterol inhibits what enzyme that catalyzes
the rate-limiting step in de novo synthesis?
What enzyme increases esterificatio and storage of cholesterol?
What kind of drugs completely inhibit HMG-CoA Reductase (and hence de
Statins _________ intracellular cholesterol signaling the cell to
________ the expression of LDLRs
What is a risk associated with BA sequestrants? What patients should
not use these drugs?
cholesterol is being excreted from the body so de novo synthesis gets
driven up as well increasing TG levels in blood. Patients with already
PCSK9 is a critical regulator of _________ activity
PCSK9 works to regulate LDL uptake by:
Mutations that inactivate PCSK9 have what effect on LDL uptake,
while gain -of-function mutations _________ it
binding to its receptor and promoting its degradation, increase it, decrease
PCSK9 inhibitors are monoclonal antibodies that prevent PCSK9 from
binding to LDLRs - this effectively prevents their degradation and
leads to an increase in the number of LDLRs available to clear LDL and
plasma LDL decreases
What is a desirable total cholesterol level?
What is a desirable LDL cholesterol level? What is considered high?
< 100, >160
What is considered low HDL? high?
< 40, > 60
What is considered normal for triglycerides? What is considered high?
< 150, > 200
The primary causes of hypercholesterolemia are familial __________
and __________ and a gain of function mutation in __________.
familial hypercholesterolemia and defective ApoB-100, PCSK9 gain of function
The primary causes of hypertriglyceridemia are familial __________
and ___________ deficiency, and a __________ deficiency
familial hypertriglyceridemia and lipoprotein lipase defiency, ApoC2 deficiency
Disorders of HDL metabolism are primarily caused by defects in ApoA1,
but can also be caused by defects in ABCA1 and LCAT, and a reduction
in CETP which reduces HDL capacity to
Secondary hypercholesterolemia can be caused by _____thyroidism,
_____stasis, and ____ use
hypo, cholestasis, drug use (corticosteroids)
Patients with excess visceral adipose tissue often have elevated ____
and low ____ levels. They often have _________ resistance as well
TGs, HDL, insulin
DM and metabolic syndrome patients are deficient in lipoprotein
lipase activity which leads to _________ of VLDL in the blood,
increase CETP activity, increase in flux of free FA to the liver
(which leads to the creation of more VLDL bc FA by themselves are not
very soluble and must be packaged)
Inappropriate growth of breast tissue can be treated with ER
antagonists such as Fulvestrant, or estrogen synthesis inhibitors
which target the enzyme ________, or selective estrogen receptor
modulators such as Tamoxifen
Estrogens interact with two nuclear receptors, alpha and beta. The
most potent naturally occuring estrogen in humans is 17-beta
_________, followed by estrone, then ________
What is the principal source of circulating estrogen in women? What
is this organ's primary secretory product?
What is the primary source of estrogen in postmenopausal women and
what is this product?
The alpha estrogen receptor is primarily expressed in the female
reproductive tract, mammary gland, hypothalamus, endothelial cells,
and vascular smooth cells. What kind of complications can this
estrogen acting on receptors in endothelial and vascular smooth cells
can lead to stroke
The beta estrogen receptors are expressed most in:
prostate and ovaries
Estrogen enters the cell by _________ diffusion and binds to an ER in
the nucleus. This binding induces a conformational change - what
determines the change?
passive, depends on the ligand
Upon binding estrogen, the ER dimerizes as homo or heterodimers:
____, ____, or _____
alpha-alpha, beta-beta, or alpha-beta
The dimer binds to estrogen receptor elements (EREs) in DNA in the
The ER/DNA complex recruits a series of proteins acting as
_____________ to this DNA region to promote __________
co-activators, gene transcription
Fulvestrant, an ER antagonist, prevents the recruitment of
co-activators so that transcription is _________. An estrogen
synthesis inhibitor will shit down this process by ___________
inactivated, cutting off supply
Both alpha and beta ERs are estrogen-dependent nuclear
transcriptional factors but have different biological functions because:
different tissue distributions, different responses to different
estrogenic compounds depending on the ligand
In bone cells, estradiol binds to the ER causing a conformational
change in the receptor that allows 2 transcriptional cofactors, X and
Y to also bind. The complex can then activate 3 genes: x-dependent,
y-dependent, and a gene that is both x and y dependent. Bc of this
estradiol is considered a
When a SERM binds to an ER it causes a different conformational
change than estradiol that allows factor x but not y so the only gene
that can be expressed is ___ dependent. This makes SERM a
x, partial agonist
Even if breast tissue only expresses transcriptional y factor, SERMs
can still act as antagonists by
competitively blocking the binding of endogenous estrogen to ERs
Tamoxifen is a SERM used to treat breast cancert by binding to ER,
causing a different conformational change that allows for dimerization
but with different proteins (co-repressors not co-activators) which
turns off transcription
Even thought Tamoxifen is an antagonist in breast tissue it is a
partial agonist in endometrium and bone. What potential complications
could this cause?
Under normal conditions, GnRH causes what kind of secretion of LH and FSH
Continuous administration of GnRH has what effect on LH and FSH
What 4 hormones are affected by menopause
E, P, inhibins A/B, activin
During menopause, estrogen and inhibins will _____________ while LH
and FSH ___________ (due to negative feedback)
Postmenopausal women are at risk for:
bone fractures, osteoporosis, CVD, memory loss/cognitive difficulties
Menopause treatment for women with a uterus is ____________ while the
treatment for women without a uterus is _________.
E & P, estrogen alone
What is the current recommended HRT for postmenopausal women?
lowest possible dose for shortest amount of time