Unit 2- Metabolic (Glucose and Fat) Flashcards
primary causes of current obesity epidemeic
genetics diet physical activity environment stress/sleep
brain and energy balance
brain helps balance E in/out while using stored fuel
doesn’t care where glucose comes from, it just wants it constant/high
not an insulin dependent organ- 1 alternative fuel, ketone
postive E balance: assimilate exogenous nutrients
neg E balance: mobilizing/utilizing stored nutrients
components of E expenditure
75% basal metabolic rate- resting E expenditure
10% thermic effect of food (obligatory and facultative)
high variability oh physical activity E expenditure
-mechanical work and waste/inefficiency plays a role
these tell you total E expenditure = E into when in E balance
TEE= 25-35 kcal/kg/day
EE in overweight individuals reporting low intake- many underreport
glucose
structure
–> glycogen
hexose monophosphate shunt
6Cs, each w/ H and OH except one CH2OH
–> glycogen
when cycle is busy and gets backed up making ATP, it can sidestep and go to fatty acid cycle or glycogen
exercise- break down glycogen (glycogenolysis)
-glycgen is like an E reserve for glucose
glucose can also go to hexose monophosphate shunt
Fatty acid
structure
long C chain w/ acid COOH group and methyl group at other end
Amino Acid
structure
alpha C w/ R group w/ amino group NH2 and COOH
can take elets (CHON) and plug into TCA cycle at various places
eventually go up to gluconeogenesis
-but need to get rid of N- it goes to urea cycle and excreted as urine/urea nitrogen
hierarchy of fuels converting grams to calories alcohol protein glucose gat
o Alcohol: 7kcal/g, no storage pool
o Protein: 4kcal/g, no true storage pool
o Glucose: 4kcal/g, storage as glycogen in liver and muscle. Muscle glycogen cannot be released as glucose
o Fat: 9kcal/g, large storage pool; you can live off our fat for a super long time
key concepts biochem pathways entropy states anabolic/catabolic redox
o Biochemical pathways are linked reactions that progressively modify a starting molec
o Entropy, overall molecs head towards lower E state, but can “collect” E from another molec
o Fed versus fasted states
o Anabolic vs catabolic (building it up vs breaking it down)
o Reduced (nutrient), oxidized (product)
liver
functions
pancreas
consumes glucose to make E
makes glucose
gluconeogenesis (opposite of glycolysis)
can both produce and consume glucose
tries to make the math work
glucose consumption via glycolysis and TCA cycle
glucose production via glycogenesis or glycogenolysis
pancreas drives when it acts as a producer and consumer
-glucose rises- insulin rises and glucagon goes down
glycolysis location steps net ATP GLUT4, GLUT2 glucokinase, hexokinase
sub cellular location- in the cyto of all tissue cells
glucose –> pyruvate
glucose enters cell via GLUT2/GLUT4 glucose 6 Phosphate (-ATP) (+hexokinase/glucokinase) G6P--> F6P F6P--> F1,6-BP (-ATP) (+PFK-1) F1,6-BP--> 2x 3C (NAD--> NADH) (+4 ATP) --> Phosphoenolpyruvate PEP PEP--> Pyruvate
glycolysis= net 2 ATP
GLUT4: insulin sensitive; in muscle and adipose tissue (want muscle to take up glucose in fed state, but brain in fasted state)
GLUT 2: not insulin sensitive; in liver and beta cells (in pancreas that secretes insulin)
glucokinase: in liver and beta cell
- liver has large capacity to take up glucose if it’s high
- glucose/enzyme activity graph is linearly inc
hexokinase: all other tissues
- enzyme activity maxes out quickly/instantly and stays low
TCA cycle general process products steps function exercise
no rate limiting step- takes whatever’s coming in and spits it
AA’s contribute
out somewhere else
products: 3 NADH, FADH2 intermediates
go to ETC in inner mito membrane
NAD and FADH then get recycled back into cycle
requires O2 (oxidative phosphorylation)
(Lactate can go to liver and turn into pyruvate)
steps Pyruvate crosse mito membrane Pyruvate--> acetyl CoA (-CO₂)(+PDH) Acetyl CoA+ OAA --> Citrate Citrate --> alpha-ketoglutarate(- CO₂)--> succinate (-CO₂)--> fumarate--> malate --> OAA
TCA cycle makes GTP–> ATP
main func is to harvest E via oxidative phosphorylation
as you exercise, ATP falls and ADP rises, which pulls NADH and FADH into cycle, and can pull in FAs and glucose if they’re around
-resp control and E regulate the TCA cycle (ATP regulates)
de novo lipogenesis
beta oxidation
lipogenesis
Acetyl CoA can turn into fatty acids
eating too many carbs can be alternatively turned into fat (fed state)
beta oxidation:
breaking down FA’s –> Acetyl CoA (fasted state)
TCA cycle- 2 CO₂’s come out, so you can’t make glucose from fat
pyruvate –> lactate
why
steps
cori cycle
helpful for a cell that doesn’t have mito (RBC,
Pyruvate–> locate (+PK)
energetically neutral rxn
driven largely by conc
NADH–> NAD
cori cycle
lactate rises when you don’t have enough O₂ to fully burn the glucose
lactate goes into liver, does gluconeogenesis, then goes back to muscle
only others that do this is RBCs- only E source is glycolysis since there’s no mito
gluconeogenesis when why steps location
make glucose from pyruvate (backwards glycolysis)
happens when insulin is low and blood sugar is dropping (fasting); going to get it from liver
want it to run when we don’t need E from pyruvate; we don’t need to burn it- we want to turn it into glucose (then maybe glycogen)
high levels of acetyl CoA (via fat oxidation) activate this cycle
E requiring process in several places
-E comes from oxidation of fat; fat comes in at acetyl CoA; liver is getting fat from adipose, coming in as acetyl CoA, and harvesting E/making ATP from burning fat in liver; now used to take lactate, AAs, and glycerol and turn them into glucose
3 regulated steps, same as glycolysis
Pyruvate goes into mito, becomes OAA (+PC), then malate, then back out, then OAA–> PEP (+PEP-CK) (-2GTP; highly regulated)
PEP–> F1,6-BP (+carbon intermediate, incl glycerol)
F1,6-BP–> F6P **(rate limiting step; direction determining) (F2,6-BP inhibits this direction; PFK2 –> F2,6-BPase)
F6P–>G6P
G6P–> glucose (+G6Pase)
glucose crosses membrane
G6Pase is only found in liver and kidney- you can do gluconeogenesis in other tissues but can’t release glucose from cell (only 2 glucose releasing locations)
glycogen
glycogenesis
glycogenolysis
glycogen
store glucose; polymer of glucose
branching enzymes make it branched to keep it in soln in liver (losing water weight on diet)
allows rapid release of glucose from polymer- easy to clip off glucose molecs
-happens in liver to prod blood glucose
-skeletal muscle to make E
want to make glycogen when insulin is high
–insulin enzyme- dephosphorylate and makes it active; want active when insulin is high
glycogenesis
G6P–> G1P
–> UDP glucose
–> glycogen (+glycogen synthase)
glycogenolysis
glycogen breakdown during exercise
glycogen–> G1P (+glycogen phosphorylase)
G1P–> G6P (+ phosphoglucomutase)
debranching enzymes takes terminal branch and sticks onto end of long chain; then another deb ranching enzymes clips off the last one to make (Glucose + ATP –> G6P)
when you have a lot of ATP, or if you have a lot of G6P/glucose you turn off glycogen phosphorylase
having a lot of ATP, glucose, or G6P will inhibit turning glycogen into G1P
glycogen synthesis is inhabited by phosphorylation (turn it off when glucagon is high)
-counterreg hormones phosphorylate
hexose monophosphate shunt HMS AKA when purpose steps
AKA pentose phosphate pathway
happens after everything is already full and you still have extra glucose
purpose: prod NADPH (syn of fats, steroids; useful as antioxidant)
G6PD deficiency = hemolytic anemias after a certain drug exposure
Glucose –> G6P
G6P–> ribose sugars (+G6PD) (+NADPH)
–> purines, pyrimidines
Km and Vmax
Km is conc to run at half Vmax
Vmax is saturation
regulation:
substrate conc
enzyme conc
allosteric modification/regulation
-some other moles will interact w/ enzymes to encourage/discourage step
covalent modification
- hormonal reg
- -insulin- hormone of fed state (tends to dephosphorylate enzymes to make more active)
- -counterregulatory CR hormones- catecholamines (adrenaline, NE, EPI, glucagon, etc) (tend to signal through cAMP to phosphorylate)
muscle fuels
choice
can take up glucose and store it as glycogen or burn it when insulin is high
or can do TCA cycle and use it for fuel
can do fat and carb metabolism
adipose tissue
in fed state- take up glucose and turn it into fat
fasted state goals liver pancreas general processes brain
need to maintain stable plasma glucose, but glucose will start to fall if you don’t eat
liver- start making glucose and stop taking it up
pancreas- glucagon secretion is going up and insulin is going down
- beta and alpha cells are sensing the falling glucose and altering ratio of hormones
- can come from glycogenolysis or AA from muscles that do gluconeogenesis
insulin is falling, and muscle is insulin sensitive, so we’re doing less glucose uptake and more fat uptake so muscle is chaining fuel and using CO₂
muscle can use glycogen stores
brain is main glucose consumer
electron transport chain ETC goal product free radicals complex 1-4 proton leak ATP synthase
trying to make ATP
oxidative phosphorylation –> 32 ATP
TCA enzymes are in inner mito membrane w/ ETC
free radicals are produced and need to be careful to not damage cell (membranes, DNA, etc)- come from too many e-‘s w/ nowhere to go (overeating and not being active); body has diff ways of detox
proteins sitting at inner mito membrane: complex 1 through 4
-collecting e’s at NADH
-acetyl CoA makes NSDH
from complex to complex and every time they give up E
ultimate e- acceptor is O₂
Complex 2-
ETC is physically linked to TCA cycle
this generates ATP via:
-e’s moving 1,3,4 and pumping H’s through the inter membranous phase
proton gradient; chem gradient w/ pot chem E
H ion goes through ATP synthase to make ATP using proton gradient
go Complex 1 to 3 via complex Q
inherent proton leak-
some H’s leake backwards (basal metabolic rate)
major O₂ consumption at rest
ATP synthase- uses H gradient and leaks H’s back into matrix to make ATP
if we don’t have ADP, there’s no place for H+’s to go, e-‘s aren’t delivered, and everything gets backed up
-if you stop exercising, everything slows down; e- flow is tightly coupled to H+ pumping
pancreas insulin secretion pancreatic islets anatomy/contents function
normally secretes 30 units insulin/day
islet of Langerhans cells contain: beta cells- make insulin alpha cells- make glucagon delta cells- make somatostatin pancreatic polypeptide PP
beta cells
glucose-stimulated insulin secretion
also secretes insulin basal level
can go right into portal circ
-liver plays central role in regulating metabolism- it sees glucose first
glucose doesn’t get diluted in whole-body blood- it goes into portal circulation and is high
(liver is seeing higher conc’s of glucagon and insulin than the rest of the body)
insulin synthesis secretion 2 phases mechanism insulin receptor actions
made by beta cells
-beta cells respond to rise in glucose and releases insulin
secreted as a pro hormone
as it is handled in cyto, it builds disulfide bonds, and C-peptide is removed in process of becoming mature insulin
-can measure C-peptide to see how much insulin a pt is making to tell DM1 vs DM2
secretion has 2 phases:
1st phase
initial phase
-as blood sugar rises, beta cells sense it, and vesicles of proinsulin get released
lost in diabetes, esp Type 2
2- new synthesis of insulin stores
occurs when sustained hyperglycemia- continued release/production of insulin
mech of secretion
as blood sugar rises, glucose enters beta cell via GLUT2 transporter (doesn’t req insulin)
glucokinase acts on it to make G6P
G6P metabolism into ATP causes release in sullen
protein/rising AAs will also inc insulin release
insulin receptor
peripheral cell responding to insulin:
water soluble hormone insulin will bind to receptor (can’t enter)
receptor will signal the cell
receptor is tyrosine kinase heterotetramer (2 alpha and 2 beta chains)
intracellular domain of receptor has a bunch of AA kinases that are phosphorylated when insulin binds to outside domain
(insulin binds to receptor and it autophosphorylates itself)
attracts insulin response substrate IRS, which has downstream receptor pathways
(metabolic pathway and mitogenic pathway- PI3K and MAPK)
insulin actions
decreases hepatic glucose output (when you eat, you want to shut off gluconeogenesis and glycogenolysis, and stimulate glucose uptake and shut off lipolysis, and inc peripheral glucose uptake, which promotes growth, regulates vascular tone, salt, and water
hormones
general
beta cells
2 types of hormones
once cell (endocrine cell) talks to a peripheral cell chemicals secreted by endocrine cell that go into systemic circulation and act on long distances
beta cells- sense glucose, release insulin as an effector to talk to peripheral cells
o Zn transporter helps bring insulin into granule/cell
o IA2 on outside of granules and helps potentiate release out into circulation (and GAD helps- not unique to beta cells)
2 types of hormones
water soluble: membrane assoc receptors on peripheral cell, which will have some sort of 2nd messenger (Fast effects)
lipid soluble: protein bound in order to float in bloodstream
goes through cell membrane and acts on nuclear receptors (ex testosterone, cortisol, aldo, etc)
affect DNA transcription (takes a while for effect)
insulin signaling pathways
2 special signaling molecs:
IRS PI3K pathway
- metabolic pathway, glucose uptake/disposal and vasodilation
- decreasing hepatoglucose output
- increasing insulin secretion
- sensitive pathway- doesn’t like sugar, cytokines, or insulin to be high
- insulin resistance knocks this side out
IRS MAPK pathway
-cell growth, mitogenesis, vasoconstriction
insulin actions
store nutrients
insulin resistance
reduce hepatic glucose output
- reduce glycogenolysis
- reduce gluconeogenesis
inc peripheral glucose disposal
- inc glucose uptake by muscle and fat
- activate glycolysis, glycogen synthesis, and de novo lipogenesis
inc fat uptake by adipose tissue
reduce fat release from adipose tissue
fed hormone insulin works against glucagon and EPI
insulin resistance
o Inc liver glucose production
o Reduced peripheral glucose disposal
o Inc fat release from adipose tissue
o Most of the time insulin resistance lives downstream
♣ Nl Insulin signaling happens when IRS get phosphorylated (pY- tyrosine)
♣ Insulin resistance appears to be nl IRS phosphorylated on different AA substrates (serine/threonine)
insulin and glucagon secretion
DM2 marked by
o Low glucose- you have high glucagon and low insulin
High sugars- you have low glucagon and high insulin, as long as cells/receptors are interpreting signals appropriately
DM2 is marked by blunted insulin response and inadequate glucagon suppression after meals
o Could be from glucose toxicity- when your blood sugar is really high it becomes somewhat toxic, but insulin deficiency is somewhat reversible
incretin effect
Give pt a glucose and measured plasma glucose over several hours either oral or IV infusion
♣ IV and oral glucose levels are the exact same
♣ It’s not same insulin though
o If you give glucose by mouth, you get way more insulin than by IV
♣ The beta cell is responding to glucose and something else (In GI tract?)
♣ Glucagon-like peptide-1 GLP-1
• Product of proglucagon gene from intestinal L cells
• Release is rapid in response to meals
• Potent insulinotrophic hormone
• Impaired glucose tolerance IGT and type 2 DM manifest w/ lower plasma GLP-1 compared to healthy controls
• GLP-1 facilitates glucose-stimulated insulin release
• Incretin, GLP-1 stimulates insulin release and inhibits glucagon release; both causing lowering of blood glucose
• Actions of GLP-1
o Lowers appetite, lowers blood sugar and appetite
diabetes
define
3 targets
Dx criteria vs nl vs pre
high blood glucose; enough to cause microvascular diseases
blunted insulin response after eating
kidneys- leak of protein into urine
nerves- neuropathy
eyes- retinopathy
inc risk for microvascular disease, but we don’t define diabetes this way
Dx criteria: fasting glucose OGTT HbA1c 2 times in absence of illness
Nl
<100
<140
<5.7
Pre
100-125
140-199
5.7-6.4
DM >126 >200 >6.5% random glucose >200 + typical symptoms
Diabetes Type 1 vs Type 2 statistics insulin ethnicity weight autoimmunity DKA FHx age of onset ketosis at onset pathophysiology associated conditions
Type 1 10-20% low insulin white's nl weight autoimmune markers DKA can happen FHx is somewhat- 10-20% peak in childhood/adolescence ketosis common path: autoimmune assoc w/ autoimmune thyroid disease; Celiac; Addison's
Type 2 80-90% IR + insulin deficiency AA, Native Americans, Hispanics, Pac islanders overweight/obese, weight loss No markers DKA not typical FHx: strongly genetic 80-90% age post-pubertal ketosis uncommon but possible path: insulin resistance assoc w/ obesity, lipid abnormalities, PCOS, NAFLD
gestational diabetes
pancreatic diabetes
gestational:
high blood sugar during pregnancy
o Occurs during pregnancy and goes away after;
important to screen between 24 and 28 weeks pregnant
o Pregnancy causes you to be very insulin resistant
pancreatic:
drink alcohol and get recurrent pancreatitis to kill off beta cells
no glucagon
low weight- exocrine insufficiency
Type 1 Diabetes general prevalence natural history tools for monitoring natural history
immune mediated disease –> metabolic disease
o Common and inc T cell mediated autoimmune disease
♣ Incidence is rising 3-5%/yr
o Assoc w/ other autoimmune diseases
o Now predictable in humans (islet autoantibodies and genes)
o Environmental determinants unknown
Large immune intervention trials are underway
Prevalence of DM1 by 20yo
o General pop 1:300
o First degree relatives 1:20
o High genetic risk general population 1:15
o High genetic risk FDR 1:4 to 1:2 (first degree relative)
o Monozygotic twins 1:3 to 1:1
o Pediatrician w/ 2000 pts will have 3-6 in practice
natural history:
o Nl individual: beta cell mass is relatively high
o Genetic predisposition: some sort of trigger (environmental?) causes you to lose beta cell mass and beta cell function
o Insulitis (beta cell injury) in the autoimmunity part
-T cell autoimmunity
o Then autoantibodies kick in and you have pre-diabetes
-humoral autoAb’s (IAA, anti-GAD65, 1A-2Ab, ZnT8, etc)
-loss of 1st phase insulin response (IVGTT)
-glucose intolerance (OGTT)
o Then clinical onset you have diabetes A1C >6.5%
monitoring natural history:
markers of immune sys response to the beta cell
- autoAb’s (islet cell autoAbs: insulin, IA-2, GAD65, ZnT8)
- T cell response (active area of research)
markers of metabolic changes
IV glucose tolerance test
OGTT
mixed meal tolerance test MMTT
Type 1 Diabetes associated comorbidities
Autoimmune
complications
Autoimmune
♣ Thyroid autoimmunity 15-20%; TSH testing
♣ Celiac disease 5-10%; TTG autoAb’s
♣ Addison’s disease 1-1.5%; 21(OH) autoAb’s
Complications
♣ Macrovascular (CVD, PVD)
♣ Microvascular (retinopathy, nephropathy, neuropathy)
♣ Psychosocial (depression, anxiety)
T1D genome-wide associations major histocompatibility complex T cell recognition major islet auto antigens DAISY study
Genome-wide associations in T1D
o Specific HLA genes (Immunity); many other immunity genes
o INS (insulin production and metabolism)
Major histocompatibility complex o HLA genes are on Chr 6 o Encode class 1,2,3 molecs o Class 1 present peptides to CD8 cells o Class 2 present to CD4 cells o Most of risk is in DQ and DR ♣ Allele: 1 DQ/DR haplotype
T cell recognition of antigen on an APC
-APc endocytosis antigen (insulin) and presents it to CD4+ T cell, which then targets beta cells
major islet auto antigens o mIAA (insulin autoantibodies) o GAA (GAD65) o IA-2 (ICA512BDC) o ZnT8 o Others
DAISY study
diabetes autoimmunity study in the young
diabetes onset: GAD and ICA512 become positive
over 10 yrs, if you have 2 Ab’s your risk is 70%; 3 Ab’s risk is 90%
–T1D is predictable!
pancreatic pathology in T1D
patchy- not all-or-none destruction
lobular beta cell destruction
islets are still there but don’t have beta cells
potential environmental trigger of T1D
accelerator hypothesis
hygiene hypothesis
Infections
♣ Viruses, immunizations
♣ No assoc b/w immunizations and islet autoimmunity- no difference in %, age of vaccinated, or age of onset
Diet
♣ Breast feeding/cow’s milk
♣ Timing of introduction of foods in infancy
♣ Omega-3 fatty acids/Vitamin D
Weight
Accelerator hypothesis
o The inc in T1D incidence has occurred parallel to inc in obesity
o Hyp: obesity causes beta cell stress and results in exposure of beta cell antigens to immune sys
Hygiene hypothesis
o We are too clean!
o Hyp: lack of immune stimulation at young age suppresses natural immune sys development leading to more allergies and autoimmune disorders
LADA on spectrum of diabetes
latent autoimmune diabetes of adulthood
♣ 30-70 yo at dx
♣ >=6 mo of non-insulin requiring diabetes
♣ presence of diabetes associated autoAb’s
♣ it’s like type 1.5 Diabetes
T1D tx
management
tx of T1D- insulin deficiency o dec glucose transport into cells ♣ GLUT4 glucose channel o Inc glucose production ♣ Glycogen, gluconeogenesis o Inc activity of hormone sensitive lipase ♣ Mobilization of FFA ♣ Beta-hydroxybuterate and acetoacetate (ketones)
management
o Wide fluctuations w/ long periods of hyperglycemia and freq hypoglycemia
o Don’t have to be perfect, but try to minimalize the fluctuations
o Intensive insulin therapy
♣ Continuous glucose monitors
♣ Continuous subcutaneous insulin infusion
prevention of T1D
primary
secondary
tertiary
Primary prevention
♣ Genetically at risk
♣ Goal is to stop progression to auto immunity
♣ Dietary intervention in infancy- study still going on, but unlikely helpful
Secondary
♣ Pts are antibody positive, but don’t have clinical disease yet
♣ Parenteral insulin does not delay development of T1D
♣ Oral insulin study- projected 4.5-5 yr delay with IAA >80; IAA >300 delay 10 yrs?
• Oral insulin doesn’t alter blood sugar, but insulin is taken up, chopped into protein, and protective cells of (cytokine) c-insulin and can inhibit beta cell autoantibodies and prevent/prolong diabetes
Tertiary
♣ Early in clinical disease
♣ Preserve beta cells and STOP complications
♣ Anti-CD3 (CD8, CD4 T cell marker) provides C-peptide preservation
• Unfortunately large phase 3 trial didn’t show benefit
♣ Abatacept (autoimmune tx) blocks costimulatory molec needed to activate T cells
• Delay inability to make own insulin ~9.5 months
Insulin is still mainstay tx; no immune therapies are robust enough
Type 2 diabetes quick statistics
DM screening
criteria for T2D screening in children/adolescents
o 29.1 million or 9.3% of US have diabetes (422 worldwide- pandemic)
♣ many are undiagnosed, and many are underdiagnosed
DM screening
o We’re screening earlier and more often
o Overweight and additional risk factors of being inactive, FHx, gestational diabetes, ethnicity/race, HTN, low LDL, PCOS, and everyone >45 yo should be screened
Criteria for screening for T2DM in children and adolescents:
♣ Overweight plus any 2:
• FHx of T2DM in 1st or 2nd degree relative
• Race/ethnicity
• Signs of insulin resistance or conditions assoc w/ insulin resistance
• Maternal history of diabetes of GDM
♣ Age of initiation 10 yrs or at onset of puberty
♣ Freq: every 3 yrs
♣ Screen w/ A1C
glucose metabolism regulation
glucose metabolism is tightly regulated
o nl conc 5 g glucose in vascular system- 1g/L; diabetics have >7g in blood
o brain and NS consumes 100-125 mg/day- it’s the main user
o the cutoffs for dx are based off of evidence of microvascular injury
type 2 diabetes
pathogenesis
o Genes and environment (decreased exercise) contribute to insulin resistance
o Which leads to dec insulin secretion
Which gives you T2DM
metabolic defects in type 2 diabetes
nonspecific
specific
Hyperglycemia tells you you have diabetes- nonspecific for which one
Specifically type 2 diabetes:
♣ Liver is making glucose despite the fact the pt already has hyperglycemia
♣ Muscle has dec glucose uptake; muscle is resistant to action of insulin telling you to store it
♣ Pancreas cells aren’t making adequate insulin for the inc in glucose in the environment
♣ Hyperglycemia makes muscle more insulin resistant
♣ Impaired beta cell function even further causes beta cell dysfunc- overwhelming
normal vs stressed insulin action
Nl: insulin receptor signaling through IRS, and in fat cell it’s storing lipids
Stress: insulin receptor is unable to signal through PI3K- you have cytokines and inflamm going on
♣ Sick, so fat cells are breaking down into FFAs, causing insulin receptors to not work well, and create a vicious cycle
♣ This can happen acutely in hospital ICU; but this can go away as soon as you have stress controlled
• Body puts insulin regulation on back burner when it’s sick, which is beneficial when you’re sick but not when you’re obese and sedentary
o You inherit insulin resistance, and then over time your beta cells fail- mainly due to genetics
♣ Blood glucose will only show insulin resistance once your beta cells stop working
beta cell func w/ T2D dx
hepatic insulin resistance
peripheral glucose uptake
Approximately 50% of beta cell function has already been lost at time of dx
o That will deteriorate over time
Hepatic insulin resistance: inc hepatic glucose output
o Nl people will go up and down between meals, and liver will compensate when we need it
o DM2’s livers will make a bunch of glucose because their liver hasn’t been shut down by insulin, even if their blood sugar level is super high
Peripheral glucose uptake
o Pts w/o diabetes had nice robust use of glucose
o Pts w/ diabetes had much smaller clearance of glucose- less able to dispose of glucose even if you give them a lot of insulin
insulin and glucagon in nl glucose tolerance fed state glow glucose fatty acids and AAs C peptide and incretin effect
Insulin and glucagon in nl glucose tolerance
o We now know that in fed state when glucose is inc, beta cells will secrete insulin
o Low glucose situation- glucagon will be secreted and stim hepatic glucose output; which recently found that can be further manipulated by the gut
o Fatty acids and AAs can also stimulate glucagon, which happens at night when you’re transitioning to a fasting state
o C peptide represents insulin secretion
♣ Incretin effect- if you give oral glucose, plasma glucose and C-peptide (insulin) goes up together; but if you do IV glucose, the same plasma glucose gives a much lower C peptide level
MODY
maturity onset diabetes of young
o Beta cell disorder
o Either glucose can’t get metabolized (glucokinase defect) or a transcription factor defect
o Hyperglycemia: chronic: readily releasable insulin pool in the granules gets depleted, so you lose 1st phase insulin secretion and later lose insulin production
Type 2 DM treatment
Pathophysiology informs tx
o Lifestyle prevents diabetes
o Diet and exercise affect glycemic
♣ Dec carb or refined carb ingestion; gives liver less work to do
♣ Exercise: by using muscle, every contraction pulls glucose into muscle for storage; deplete glycogen storage so glucose can be utilized; muscle and fat will in general become more insulin sensitive- good thing
o Brain, gut, kidney, liver all having their own demands/methods causing hyperglycemia
carbohydrate regulatory proteins
carbohydrate counterreg proteins
carbohydrate regulatory proteins
♣ insulin (only hormone that decreases glucose*- new research on FGFs though)
• pancreatic beta cells
• stimulates glycogen storage in the liver
• decreases hepatic gluconeogenesis
• stimulates glucose uptake and utilization in muscle and fat
carbohydrate counter-regulatory proteins (inc glucose)
♣ glucagon: pancreatic alpha cells
• stimulates glycogenolysis in the liver
• hepatic release of glucose
♣ EPI
• Stims glycogenolysis from liver
• Inc peripheral insulin resistance
• Primary defense against hypoglycemia in T1 diabetics
♣ Cortisol and growth hormone
• Raise blood glucose much more slowly
• May be helpful in recovery from prolonged hypoglycemia
Diabetic ketoacidosis
pathogenesis (hormonal)
ketone body production (biochem)
hyperosmolar hyperglycemia syndrome HHS
♣ 10-15 cases every 1000 pt-yrs
♣ most cases occur in pre-dx diabetes
♣ fatality rate of almost 10%
• DKA unrecognized as the clinical presentation of T1DM in children
• Precipitated by severe illness: sepsis or MI in adults
♣ Can’t get DKA unless you have low insulin or high glucagon/ CR response
Pathogenesis of DKA (hormonal) o Absolute or relative lack of insulin o Inc counter-reg hormones ♣ insulin deficiency ♣ activated lipolysis (adipose tissue) ♣ inc plasma FFA ♣ inc liver fatty acids accelerated ketogenesis (occurs in the mitochondria DKA)
Ketone body production (biochemical)
o Inc FFA flux from adipocytes
o Intrahepatic glucagon/EPI induced inc carnitine acyltransferase and dec malonyl CoA activity permitting mitochondrial ketone body production (this needs to be reversed to clear DKA)
Hyperosmolar hyperglycemia syndrome HHS
o Osmotic diuresis
o Dec free water
DKA and HHS
precipitating factors
history
exam
precipitating factors DKA: no insulin in pt w/ known T1DM (20%) or new-onset T1DM (25%) ♣ New dx ♣ Eating disorder ♣ Fear of weight gain ♣ Fear of hypoglycemia ♣ Rebellion ♣ Stress of chronic dz ♣ Insulin pump failure
HHS:
♣ New-onset DM in elderly
♣ unawareness of thirst
♣ restricted water intake
o Omission of insulin o Infection o New-onset o Unknown o MI, CVA, PE, mesenteric thrombosis o Acute pancreatitis o ARF/HD/uremia o Thyrotoxicosis, Cushing’s, acromegaly o Meds: glucocorticoids, thiazides, dobutamine, antipsychotics, cocaine o Burns
History
Symptoms of hyperglycemia: polyuria, polydipsia, weight loss, weakness
o DKA:
♣ Rapid-onset hours after precipitating event(s)
♣ Nausea and vomiting
♣ Abdominal pain which correlates with severity of acidosis
♣ 30% may present with hyperosmolarity
o HHS
♣ Insidious onset - days or weeks
♣ Only 30% become comatose
♣ Altered MS usually not seen unless Sosm>320
♣ Less frequent: focal neurologic deficit, seizure disorder
Exam o Signs of hypovolemia ♣ Poor skin turgor ♣ Tachycardia ♣ Hypotension, esp. orthostatic o Altered mental status o Absence of fever even with infection because of peripheral vasodilation o Hypothermia - poor prognostic sign o DKA ♣ Hematemesis from GI hemorrhage ♣ “Acetone” breath ♣ Kussmaul respirations with more severe acidosis o Functional ileus* o Coma (more in HHS)
DKA labs and findings
Labs o Fingerstick glucose o Urine ketones (dipstick) o Initial ABG o Plasma glucose o Serum ketones o BUN, creatinine o Urinalysis o CBC with diff o EKG o Cultures – urine, blood, etc. o CXR o (HbA1c) o ELECTROLYTES***
o Calculate AG
o = Na+- Cl- - HCO3-
o Correct Na+ for high glucose
o Na+ + 1.6 x (Glu–100)/100
o Calculate effective serum osmolality
o = 2(meas Na+) + Glu/18
Lab findings- not sure if she actually went over these things in lecture
o inc WBC. If >25,000, more likely from infection
o dec Na+ (hyperglycemia causing water shift from IC to EC space)
o inc K+ (shift to ECF from insulin deficiency, hypertonicity, acidemia)
♣ Deficit as great as 500-700 mEq
♣ If not elevated, pt. has SEVERE total body K+ deficit. Needs close cardiac monitoring and aggressive K+ replacement since insulin will lower K+ further
♣ EKG can confirm that the intracellular K+ not elevated
o inc lipase, amylase can occur from DKA per se
♣ ? non-pancreatic (e.g. parotid)
DKA tx
goal
IV
insulin
Goal: stop ketone body production
IV fluids (rehydration will decrease counter -regulatory hormones)
♣ Glucagon blocks glycolysis by decreasing levels of fructose 2,6 biphosphate
♣ Glucagon inhibits Acetyl CoA carboxylase and decreases Malonyl CoA, this leaves CPT 1 active and FA enter the mitochondria for ketone body production.
Insulin
♣ Lowers plasma glucagon levels
♣ Decreases FFA and AA flux from the periphery
♣ Enhances peripheral utilization of glucose
hypoglycemia
nl
symptoms of hypoglycemia
pt profile
Normal fasting blood glucose is 70 to 115 mg/dl
Symptoms of hypoglycemia usually begin when the plasma blood glucose falls to 50 or 60 mg/dl ♣ vary from patient to patient ♣ may lessen with duration of diabetes ♣ Will be severely* blunted with frequent hypoglycemia o Adrenergic ♣ Sweating ♣ Tremor ♣ Tachycardia ♣ Anxiety ♣ Hunger o Neuroglycopenic ♣ Dizziness ♣ Headache ♣ Decreased mental activity ♣ Clouding of vision ♣ Confusion ♣ Convulsions ♣ Loss of consciousness- can crash your car
Type 1 diabetes»_space; type 2 diabetes
o Hypoglycemia is about 2-3xmore common in patients trying to normalize blood glucose with intensive insulin regimens (DCCT) targeted to prevent diabetic complications
o Insulin»glyburide>other oral sulfonylureas >repaglinide>metformin, thiazolidinediones, alpha glucosidase inhibitor (Later agents rarely cause hypoglycemia if used alone)
ideal basal/bolus insulin absorption pattern
It’s easy to get the insulin dose wrong and cause hypoglycemia
Ideal Basal/Bolus Insulin Absorption Pattern
o Ideally, what is needed is:
o A short-acting insulin with immediate onset and a shorter duration of action; and
o A long-acting insulin that provides consistent insulin availability—sufficient to prevent interruptions in basal insulin levels.
Currently these two preparations are in development (short-acting insulin aspart and long-acting insulin glargine), and it is anticipated that they will be available in 2000.
hypoglycemic unawareness
hypoglycemia not due to diabetes
DDx of hypoglycemia in adults
Hypoglycemic unawareness: hypoglycemia begets hypoglycemia
o Loss of adrenergic warning signs
o Altered mental status with no warning
o More common in patients who have frequent hypoglycemia
♣ alterations in delivery of glucose to the brain
♣ Blunted counter-regulatory response
o Treatment: avoidance of hypoglycemia for 3 or more weeks
Hypoglycemia not due to diabetes
o Fasting hypoglycemia is more sig than reactive (postprandial) hypoglycemia
♣ Whipple’s triad: not all low blood glucose is clinically relevant
• biochemical hypoglycemia
• with symptoms
• relieved by glucose
DDX of hypoglycemia in adults
o Drugs or factitious
♣ Insulin: High insulin, low C-peptide
♣ Oral anti-diabetic agents (sulphonlyureas):
o High insulin, high C-peptide
♣ C-peptide differentiates between endogenous or exogenous hyperinsulinemia because C-peptide is co-secreted in equimolar amounts with endogenous insulin
o Hypoglycemia not due to diabetes ♣ Insulinoma ♣ Ethanol • Interferes with gluconeogenesis ♣ Non--cell tumors • Large mesenchymal tumors, hepatoma, etc. • Production of IGF-I or IGF-II ♣ Severe liver disease ♣ Adrenal insufficiency ♣ Renal failure (kidneys make up to 25% of glucose produced by the body)
multiple endocrine neoplasia
MENI
MENII
MEN I ♣ Pituitary adenoma • Prolactin, GH, ACTH ♣ Parathyroid (97%) ♣ Pancreas • Gastrin (40%0 • Insulin (10%) • Glucagon, VIP
MEN II ♣ Parathyroid (hyperplasia) ♣ Thyroid (medullary Cancer) ♣ Adrenal (Pheo) • (MEN IIb: mucosal neuromas, marfanoid, low incidence of hyperparathyroid)
burden of diabetes in US
cost
morbidities
Cost- #2 in total costs to US healthcare system; $216 billion if you include pre-diabetics
Morbidity-
♣ Diabetic cardiovascular disease
• 2- to 4-fold higher risk of heart disease in diabetes
♣ Diabetic retinopathy
• #1 cause of blindness in working-age adults
♣ Diabetic nephropathy
• #1 cause of end-stage renal disease
♣ Diabetic amputations
• #1 cause of nontraumatic lower-extremity amputations
diabetic complications list
microvascular disease metabolic syndrome lipid and lipoprotein abnormalities in diabetes cholesterol HTN diabetes related procoagulant state diabetes-induced activation of PKC retinopathy nephropathy diabetic neuropathy
diabetes complications
microvascular disease
♣ (AKA: MI, stroke, peripheral vascular dx)
♣ 16 million Americans have diabetes
♣ CVD is the leading cause of death in diabetes
♣ Most common reason for hospitalization
♣ 2-4 times more common than general population
♣ more common, more severe, more deadly
♣ Ischemic heart disease is main cause of death in people w/ diabetes by a big margin
♣ Survival post-MI is lower, esp in women
diabetes complications
metabolic syndrome
Factors accelerating atherosclerosis in diabetes
• Insulin resistance leads to: o Hyperinsulinemia o Glucose intolderance o Increased triglycerides--? Small, dense LDL o Dec HDL cholesterol o Inc PAI-1 o Inc BP
• And all of these cause macrovascular disease: eg, coronary heart disease
diabetes complications
lipid and lipoprotein abnormalities
cholesterol
♣ Hypertriglyceridemia (VLDL, IDL, remnants) ♣ dec HDL cholesterol ♣ Lipoprotein composition • inc TG • inc cholesterol/lecithin ♣ Glycation/oxidation ♣ Small dense LDL ♣ inc Lp(a) (renal disease)
cholesterol lowering in diabetes: pts w/ diabetes should be tx as though they have CVD
♣ Decreases plaque progression by 50%
♣ Decreases nonfatal CV events by 40%
♣ Decreases mortality by approximately 30%
♣ By the new cholesterol management guidelines all people with diabetes between that ages of 40-75 should be on a statin
• This lecturer says EVERYONE should be on a statin
diabetes complications
HTN
HOT
♣ Definition: SBP>140 and/or DBP>90
♣ Quoted target (JNC VIII): 140/90*
♣ Quoted target (ADA): 140/80 (90)*
♣ DOD 140/90 (has best evidence)
♣ This is a moving target
♣ *130/80 w/ proteinuria
♣ HTN contributes to all complications of diabetes
HOT (hypertension optimal tx)
♣ 67% risk reduction in diabetic pts for CV mortality (events per 1000 pt-yrs) if diastolic P <80 mmHg
diabetes complications
diabetes procoagulant state
♣ cytokines, insulin, high glucose, modified LDL, modified VLDL can lead to ultimately inc activated plts, plasminogen, tPA, and inc fibrin deposits
diabetes complications- TREATMENT
Treat cholesterol, HTN, and glucose levels**
diabetes complications
microvascular
♣ Retinopathy
♣ Neuropathy
♣ Nephropathy
♣ *primarily caused by elevated blood glucose
♣ if you control someone’s blood sugars, their risk reduction goes down for any diabetes-related endpoint
♣ polyol pathway- inc glucose leads you to inc sorbitol then inc fructose
• inc therapeutic target?
♣ Advanced glycation end-products
• Interfere with basement membrane function
• Squelch nitric oxide and impair vasodilation
• Bind to AGE cellular receptors
o Production of matrix proteins such as type IV collagen by renal mesangial cells
o Expression of adhesion molecules on endothelial cells
o Production of growth factors such as VEGF
• Intracellular AGEs can crosslink and disrupt DNA function and repair.
diabetes complications
diabetes induced activation of PKC
Hyperglycemia leads to:
• Oxidative stress
• Advanced glycosylation end products
• Diacyglycerol generation
♣ these lead to PKC activation
♣ PKC activation leads to retina, vasculature, kidney, and heart
diabetes complications retinopathy -pathogenesis stages prevention additional ocular complications
Diabetes is the leading cause of blindness in the U.S.. By ten years duration of diabetes, approximately 90% of individuals with diabetes will have some degree of retinopathy.
Pathogenesis
• Pericyte drop-out
• Loss of autoregulation of blood flow to the retinal capillary bed.
• Capillary drop-out
• Basement membrane thickening
• Leakage of intravascular fluids leading to soft and hard exudates
• Hypoxic stress and local production of cytokines and growth factors (vascular endothelial growth factor-VEGF)
• Neovascularization and proliferative retinopathy.
Stages of diabetic retinopathy • 1. Early preproliferative • 2. Mild preproliferative • 3. Severe preproliferative ** (time for intervention) • 3. Early proliferative • 4. Neovascularization disc/elsewhere • 5. Macular edema
retinopathy is preventable
• Annual ophthalmologic examinations permit identification of individuals with progressive retinopathy. Two large multi-center studies have proven that early intervention at this stage with panretinal photocoagulation can prevent or decrease visual loss.
• The Diabetes Control and Complications Trial and the UKPDS have established that tight glycemic control can prevent or delay retinopathy
• Early intensive control gives you legacy effect- both micro and macrovascular perspectives
Additional ocular complications of diabetes
• Macular edema *
o most common complication of the eye in type 2 diabetes
o Photocoagulation, steroids, and VEGF inhibitors all effective
• Corneal ulceration
• Glaucoma
• Cataracts
diabetes complications
neophropathy
pathogenesis
♣ Diabetes was listed as the primary cause of kidney failure in 44% of all new cases in 2011.
♣ 35% of diabetic pts will dev diabetic neophropathy
♣ often a long preclinical phase w/ nl or supranormal GFR
♣ proteinuria is critical marker of impending seirous renal disease
♣ without tx decline in GFR is rapid
♣ 5-10% of pts w/ diabetes req dialysis
♣ once started on dialysis only 20% of diabetic pts will be alive in 5 yrs
pathogenesis
• Hyperfiltration (secondary to the increased osmotic load of hyperglycemia)
• Intrarenal and peripheral hypertension
• Basement membrane thickening
• Mesangial proliferation
• Glomerular obliteration
♣ You can slow progression via ACE inhbitiors, ARBs, protein restriction, and tight glucose control
diabetes complications neuropathy mononeuritis multiplex distal symmetric polyneuropathy autoimmune diabetic amyotrophy diabetic foot disease CNS problems
Mononeuritis multiplex
Can present w/ ptosis or something that looks bad, but not as bad as you think- good news bad news
Distal symmetric polyneuropathy
• Most common, but the others can look like storke or something very bad, so you want to recognize that DM can be the contributer
• More in pts who are taller- longer the nerve is the more possible it is to be bathed in high glucose and injury
• May first present in tingling, numbness, hyperalgesia, but then when pain goes away (good news) but then you can’t feel feet (bad) or lose feeling in your hands- very disabling
Autonomic neuropathy
Diabetic amyotrophy
Diabetic foot disease
• Diabetes is associated with impaired blood flow and sensation to the extremities. This leads to a high incidence of mechanical trauma and infectious complications leading to amputation and hospitalization. This complication is largely preventable by appropriate footwear, examination and education.
• Amputations
o About 60% of non-traumatic lower-limb amputations among pts >20 yo have been dx w/ diabetes
o Contractures- hammer toe- improper weight bearing- ulcer- infection – osteomyelitis- amputation
CNS problems- men can lose erections
diabetes complications
summary
o Diabetes is common and the complications are devastating AND preventable
o Diabetic cardiovascular disease
♣ 3 to 5-fold higher risk of heart disease in diabetes
o Diabetic retinopathy
♣ #1 cause of blindness in working-age adults
o Diabetic nephropathy
♣ #1 cause of end-stage renal disease
o Diabetic amputations
♣ #1 cause of non-traumatic lower-extremity amputations
insulin
who needs it?
ALL pts w/ T1D
many (advanced) pts w/ T2D
insulin
available products to purchase
insulin analogs
most available as U100 (100 units/mL) in 10mL vials
0.3, 0.5, and 1.0 mL syringes
High conc’s (lower vol’s) are absorbed better, so more effective
insulin pens
Rapid acting insulin analogs are made by modifying human insulin
♣ Human insulin w/ A chain and B chain
♣ Lispro- proline and lysine were reversed
• Forms monomers more quickly than human insulin
♣ Aspart
♣ Glulisine
• AA substitutions in both/all of these
Rapid acting insulins
lispro (Humalog)
Aspart (Novolog)
Glulisine (Apidra)
“no LAG”
o Onset of action 5-15 min o Peak 1-1.5 hr o SQ injection or insulin pump o Given just prior to a meal o Dissociates rapidly into monomers after injection
rapid acting inhaled insulins
Afrezza
o Onset of action: 5 min o Peak 1 hr o Duration 2 hrs o Set-dose cartridges for inhalation device o Administered just prior to a meal o
Can dec pulm func, can’t used w/ asthma or COPD
short acting insulins
“Regular”
Humulin R; Novocain R
o Onset of action: 30-60 min o Peak 2 hr o Duration 6-8 hrs o SQ injection, IV infusion o Inject 30 min before eating o Difficult to time correctly, and lasts too long
intermediate acting insulins
NPH
o Onset of action 1-3 hr o Peak 6-8 hr* difficult o Duration 12-16 hr o SQ injection only ♣ >=2x/d for basal coverage ♣ cloudy soln – the only one that’s supposed to be cloudy
long- acting insulins
• glargine (Lantus), Detemir (Levemir), Degludec (Tresiba)
o onset of action: 1-1.5 hr
o no pronounced peak
o duration 24 hr (glargine); 12-20 hr (detemir), 42 hr (degludec)
o SQ injection only
o Cannot be mixed in the same syringe w/ any other insulins
pre-mixed (biphasic) insulins
Mixture of intermediate- and short- or rapid-acting insulins- basal AND meal insulin needs
Used 2x/day just before AM and PM meals
o SQ injection only
Insulin analog premixes: inject 15 min QAC
♣ Intermediate plus homolog: 75/25, 50/50
♣ Intermediate plus novolog: 70/30
NPH + regular: inject 30 min QAC: 70/30, 50/50
insulin usage caveat
mimic attempt
the actual pharmacokinetics of injected insulin may vary
o Volume
o Conc
o Body site (thigh vs abdomen vs upper arm)
o Presence of lipodystrophy
o Intradermal vs subcutaneous (ideal- abdominal fat)* vs intramuscular
♣ Esp if site is warm, rubbed or exercised
We try to mimic the same normal profile of inc in insulin w/ inc in glucose (delta 30-50mg/dL)
o MDI- multiple day injection therapy
o Basal bolus
o Intensive insulin therapy
o Basal insulin
♣ Insulin taken to suppress hepatic glucose production and to maintain normal fasting blood glucose levels
o Bolus/prandial insulin
♣ Insulin taken to cover rise in glucose from a meal: fixed dose OR according to carb content of meal
♣ Lispro OR aspart OR glulisine OR inhaled insulin before each meal
o Correction dose insulin
♣ Insulin taken to correct pre-meal hyperglycemia
• Using rapid-acting insulin
• Often added to meal/prandial dose
• Can be taken alone (in between meals)
• Caution: do no “stack” corrections
insulin tx for Type 1 Diabetes
insulin options
insulin pump
artificial pancreas
Use long acting insulin (glargine) 1x/day and 3 short-term per day
Detemir 2x/day and same 3 injections of rapid acting insulins
CSII continuous subcutaneous insulin infusion therapy (insulin pump)
♣ Dosage instructions are entered into the pump’s small computer and the appropriate amount of insulin is then injected into the body in a calculated, controlled manner
Advantages
• Eliminates multiple daily injections
• Different basal rates (“dawn phenomenon” or “workweek/weekend”)
• Small increment boluses are possible
• Different bolus types (Square vs dual wave)
Caveats • Upfront cost • Significant training • Motivation • Ability to troubleshoot • Interruption of infusion or “bad site” can lead to major problems (DKA) within hours
Artificial pancreas ♣ “closed loop system” ♣ “bionic” pancreas ♣ FDA- approved in sep 2016 ♣ Continuous glucose monitoring combined w/ insulin pump that maintains nl glucose w/o much intervention by the pt
insulin tx for Type 2 diabetes
when?
always if
When ♣ If lifestyle modifications and non-insulin combinations don’t achieve target A1C ♣ Or if contraindications to other meds • Renal or heaptic dysfunc • CHF
ALWAYS if: Signs of insulin deficiency on presenation o Weight loss o Fasting blood glucose >250 o Random blood glucose >300 o A1C >10%
Hospital admission for diabetic emergency
o Hyperglycemic hyperosmolar state
o Diabetic ketoacidosis
pt and physician barriers to insulin therapy
Pt
♣ Fear of intections, hypoglycemia, gaining weight
♣ Believe that insulin means serious DM
♣ Belief that insulin causes blindness, etc
♣ Inconvenience, stigma
Physician
♣ Uncertainty about whether insulin is really necessary
♣ Difficulty initiating and adjusting therapy
• Time, experience, staffing
♣ Fear of hypoglycemia, or inducing weight gain
glucose and A1c targets
o Fasting BG 70-130
o 2 hr post-meal BG <180
o A1C <7%;
<7.5% in childhood/adolescents,
<8% in severe hypoglycemia, severe comorbidities or complications, limited life expectancy,
<6.5% in pt w/o significant comorbidities
approach to management of hyperglycemia
o Risks potentially assoc w/ hypoglycemia and other ADRs
o Disease duration, life expectancy, important comorbidities
o Estimate vascular complications
o Potentially modifiable: pt attitude and expected tx efforts; resources and support sys
starting insulin therapy in type 2 diabetes
adjusting insulin therapy
paradigm for adjusting insulin
Starting:
o Low complexity would be 1 injection/day, but less flexible
o High complexity: multiple (3) injections/day, but more flexible
o Typically start w/ single basal injection per day along w/ non-insulin agents
adjusting:
NPH QHS or glargine/detemir QD: 10 units or 0.1-0.2u/kg
♣ Check fasting BG every morning (QAM)
♣ Inc dose by 2 units q3 days unitl <130 mg/dL
• If fasting BG >180, inc by 4 units q3 days
check HbA1C q3 months
if HbA1C is <7% after 3 months, continue same regimen
if not (but fasting BGs are at goal), check BG pre-lunch, pre-dinner, and HS
♣ add a 2nd injection of rapid-acting insulin at the appropriate time, 4 u to start, and inc by 2 u q3 days until BG <130 mg/dL
if hypoglycemia occurs or fasting glucose <70 mg/dL, reduce bedtime insulin dose by at least 10%
paradigm eliminate the lows first ♣ when is it happening/why ♣ ROS and BG records ♣ Reduce total daily dose of insulin by at least 10-20% in a targeted way
Eliminate the highs
♣ When and why
♣ ROS and BG records
♣ Inc total daily dose of insulin by 10-20% in a targeted way
tools for monitoring blood sugar
Glucometers ♣ Quick results (seconds) ♣ Fasting, pre-lunch, pre-dinner, bedtime • At leas 2x/day • Optimally 4x/day • Some pts check 7-10x/day ♣ Some can help calculate doses
Continuous glucose monitors
♣ Very useful in pts w/ frequent hypoglycemia
inpatient hyperglycemia
causes- PMH, stress, meds, etc
mangement
causes:
Pre-existing diabetes, DKA, HHS, gestational diabetes
Stress hyperglycemia
♣ Medical illness, trauma, burns, surgery
Medications: glucocorticoids
♣ Solid organ transplant, pulm/neurosurgery pts, chemo, bone marrow tx
Enteral, parenteral nutritional therapy
Renal disease, esp on dialysis
Cystic fibrosis-related diabetes
Managed w/ insulin therapy
♣ Stop non-insulin glucose-lowering agents in almost all pts being admitted hospital
♣Critically ill
• If insulin is needed, use IV
• Close glucose monitoring, hypoglycemia protocol
♣Non-critically ill
• If insulin is needed, use scheduled insulin doses
• Glucose monitoring 4x/day, hypoglycemia protocol
♣Re-evaluate insulin regimen daily
take home points for insulin therapy
All pts w/ T1DM need it
♣ Intensive insulin therapy is standard of care***
♣ Insulin analogs work better and provide flexibility- meals, activity
Many pts w/ T2DM also need it
♣ Hospitalization for severe hyperglycemia
♣ Signs/symptoms of insulin deficiency
♣ Inadequate control on or contraindication to other agents
Can be combined w/ noninsulin therapies
Knowing the insulin lets you choose the right ones in regimens that make sense for your pt
non-insulin therapies for diabetes
lifestyle
med classes
Lifestyle changes- FIRST
reinforcement/edu/goal-setting at every visit!
♣ Less calorie-dense foods
♣ More complete carbohydrates
♣ Higher fiber, lean proteins, smaller portions
♣ Inc physical activity
♣ Weight loss if overweight
Medications • Glucose-lowering medications- therapy classes o Sulfonylureas o Recombinant human insulin o Metformin o Acarbose o Insulin analog (Humalog) o T2D o Repaglinidine o Exenatide o Pramlintide o Sitagliptin o Canagliflozin
metformin class action risks pros cons
Biguanide
Potentiates the suppressive effect of insulin on hepatic glucose production
• Suppresses hepatic glucose output
Does NOT stimulate insulin secretion OR inc circulating insulin levels
Risk of lactic acidosis lower than a different drug in this class- pulled off US market for fatal cases of lactic acidosis
Recent update: use eGFR to guide use
Pros
• MOA- not increasing insulin production (suppressing glucose output- attacking a root cause)
• No hypoglycemia
• Inexpensive ($4)
• No weight gain
• Combination pill with:
o Fulfonylureas, thiazolidineodiones, DPP-4 inhibitor, SGLT-2 inhibitor
Cons
• Side effects: GI (nausea, bloating, diarrhea)
• Risk of lactic acidosis with:
Contrast media, CHF, renal insufficiency, liver disease
deciding the next agent to give after metformin A1c weight issue, injections CV comorbidities insurance problems renal func/hepatic disease
mainly a problem of insulin production
mainly a problem of insulin resistance
either or both
♣ What is the pt’s A1C?- insulin if high
♣ Is weight an issue? Is the pt willing to do injections? If yes to both, GLP-1RA
♣ If not willing to do injections, SGLT2-i
♣ CV comorbidities?
SGLT2-I or GLP-1RA (some preliminary support for CV benefit)
♣ If insurance requires/restrictive formulary, sulfonylurea ($4)
Eligible for any co-pay cards/discount programs?
♣ Metformin ($4)
♣ Sulfonylureas ($4)
♣ Insulin (NPH, regular)
Compromised renal func or hepatic disease?
♣ Insulin- basal initially, possibly also bolus
Mainly a problem of insulin production? ♣ GLP-1RA ♣ Insulin ♣ Sulfonylurea ♣ (DPP-4i)
mainly a problem of insulin resistance? ♣ Metformin ♣ GLP-1RA ♣ DPP-4i ♣ TZD ♣ Insulin
Either or both
♣ SGLT-2i
A1c
define, measures
standard of care
metformin, insulin, sulfonylureas’ lowering capabilities
monitoring glycemic control
o Glycosylated hemoglobin “A1c”
o Measure of avg blood glucose over the period of 2-3 months
Standard of care to:
♣ Measure this periodically (2-4x/yr) in ALL pts w/ diabetes
♣ Target certain levels to reduce risk and delay progression of complications
o Metformin can lower A1C 1-2%
o Insulin can lower 1.5-3.5 or more
o Sulfonylureas 1-2
o All others are as little as half a percent
incretins 2 (3?) types secreted by when does it work? incretin effect
GLP-1 (glucagon-like peptide 1)
♣ Very effective for lowering glucose in diabetes
GIP (gastric inhibitory peptide)
DPP-4 inhibitors
Secreted by L and K cells in GI tract to response to food intake
Augments insulin secretion only if blood glucose is elevated
Incretin effect is reduced in T2D
o If you infuse glucose IV vs via mouth, you get different effects
o If you have same blood sugar (glucose levels), but very different insulin concentrations
♣ Food by mouth- 2-3 fold higher insulin conc’s
♣ Food by IV is much lower
o Incretins potentiate insulin production in response to oral food consumption
o Insufficient insulin secretion and glucagon suppression in response to a meal in T2D
♣ Glucagon is a counterreg hormone for insulin, so it makes sense
• Glucagon either stays the same or goes up, but is not suppressed appropriately
incretin acting meds also act on brain and GI in glucose homeostasis
never give the 2 incretin enhancers together at the same time- inc risk of side effects
GLP-1 mech's agonist names pros cons DPP-4
lowers glucose via several mech’s
Food intake stimulates GLP-1 secretion by L cells of ileum
• Stimulates glucose-dependent insulin secretion by pancreas
• Also suppresses postprandial glucagon secretion by alpha cells in pancrease
• Both of these decrease hepatic glucose output
GLP-1 also slows gastric emptying and increases satiety (inhibits food intake)
• Both of these also help normalize blood glucose
GLP-1 alone is not a useful med
• Native GLP-1 peptide is rapidly cleave and inactivated by DPP-4 within minutes of appearing in circ
GLP-1 agonists:
o exenatide, liraglutide, exenatide Qwk, albiglutide, dulaglutide
Pros • Multiple MOA to lower postprandial glucose • Effects are glucose-dependent • Weight loss • Recent trial suggesting CV benefit
Cons
• SC injections
• Side effects
• Expensive
DPP-4 inhibitors MOA names pros cons
DPP-4 inhibition inc T1/2 of endogenous GLP-1 and GIP
DPP-4 inhibitors:
o Sitagliptin, saxagliptin, linagliptin, alogliptin
Pros ♣ Multiple MOAs to lower postprandial glucose ♣ Oral ♣ 1x/day ♣ weight neutral ♣ combination pill w/ metformin
cons
♣ less potent of glucose-lowering effect
♣ expensive
♣ side effects
sodium glucose co-transporter 2 inhibitors names nl individual filtering, urine glucose MOA pros cons
Canagliflozin, dapaglifloxin, empagliflozin
Nl individuals:
♣ Filtered glucose load: approx. 180 g/day
♣ Urinary glucose: <0.5 g/day
♣ Glucose reab occurs in proximal tubule through the action of SGLT1 and SGLT2
SGLT-2 inhibitors block glucose reuptake in the kidney
♣ You start to waste glucose in urine
♣ In pts at a blood sugar of 180-200 mg/dL, they’re at capacity, kidneys can’t reab glucose after that
♣ These inhbitors lower the threshold to about 100, so you reduce glucose reab even more and excrete via urine
♣ Causes you to lose ~100 g (400 cal) of glucose
Pros • Novel mech for controlling glucose • Weight loss • Pill • At least 1 available as combo pill w/ metformin • Recent trial suggesting CV benefit
Cons • Inc risk for urinary tract and GU infections • Inc risk for hypokalemia • Expensive • ?? long term safety
insulin secretagogues: sulfonylureas names MOA pros cons
glyburide, glipizide, glimepride
once you remove pancreas it doesn’t work
o these meds close ATP-sensitive K channels in beta cells
♣ when you have glucose that gets taken up by beta GLUT2 transporter, inc ATP/ADP ratio and closing K channel, but sulfonylureas bind directly to K channel, which depo’s membrane, causes Ca to flow in, and insulin secreted out of cell; doesn’t care what glucose level is***
♣ act on beta cells to inc insulin secretion
pros
♣ inexpensive
♣ combination pills available w/ metformin, thiazolidinediones
cons
♣ weight gain
♣ hypoglycemia
♣ loses effectiveness with longer duration of diabetes
clinic visits for diabetes care and using appropriate tx’s
clinic visit- diabetes care o HbA1c monitoring o Review of home blood glucoses o Education- hypoglycemia, hyperglycemia, glucose-lowering meds o Screen for complications
using noninsulin therapies to lower glucose therapies to lower glucose in diabetes
o good glycemic control reduces complications
o many diff meds are available to control glucose
o understanding mech’s, knowing the available therapies and their pros/cons allows you to recommend and combine the right ones for your pt
o individualizing the A1c goal is important
o edu and self-monitoring improve glucose control
o appropriate preventative care lowers the risk for complications in your future pts
glucose, fructose, galactose structures
sugar alcohols
classes of carbohydrates
Structures
o Glucose- terminal COH
o Fructose- ketone on 2nd carbon
o Galactose- diff C stereochemistry w/ glucose
Sugar alcohols
o Show up as carbohydrates; all alcohols; body doesn’t absorb (sorbitol)
Classes of carbohydrates
Monosaccharides (glucose, galactose, fructose)- 6 C
Disaccharides (sucrose, lactose)
Polyols (sugar alochols- sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates)
Oligosaccharides (3-9 molecs)
♣ Malto-oligosaccharides (maltodextrins)
♣ Other oligosaccharides (raffinose, stachyose)
Polysaccharides (9 molecs)
♣ Starch (amylose, amylopectin)
♣ Fiber (cellulose, hemicellulose, pectins)
• Starch vs cellulose- different only in stereochemistry
anatomy of a grain of wheat
o Outer coating to prevent drying out (cellulose)
o Digestable/absorbable starch in the middle
o Whole grains- have mix of both
glycemic index/glycemic load cellulose refined carbs glycemic load usefulness low, intermediate, high GI ex measures \_\_ response variability
Eating cellulose doesn’t have high glycemic index- not absorbable
Refined carbohydrates- increase blood sugar; high glycemic index
Glycemic load- a way to measure quality of starch in diet
Low GI (below 55) ♣ Sourdough break, apple juice, pumpernickel, oatmeal, pasta, indian basmati rice
Intermediate GI (56 to 69) ♣ Croissant, coca-cola, raisin bran, wholemeal bread
High GI (above 70) ♣ White bread, corn flakes, doughnut, white rice
Glucose measure does not measure fructose, only glucose
Glycemic responses vary a lot by person to person; can’t predict; interpersonal variability but not intrapersonal
features of a diet that might predispose to insulin resistance
Relative amounts of fat or carbohydrate
Type of carbohydrate ♣ Sucrose, fructose ♣ Glycemic index and glycemic load ♣ Amylose, resistant starch, and fiber ♣ Whole rains, vegetables, legumes
Total calories, positive energy balance
types of studies to inform nutritional behaviors animal or in-vitro epidemiology short term intervention long term intervention data on food intake patterns
Animal or in vitro studies
♣ Can provide the most detailed mechanistic information
Epidemiological studies
♣ Population based intake data
♣ Nurses health study and health professionals follow up study, iowa women’s health study
♣ Issues: validity of intake data, reliability of IR dx, interraltionship of factors
Short term intervention studies
♣ More definitive than epidemiological studies
♣ Problems with power, diet control, and endpoint
Long term intervention studies
♣ Most definitive type of study
♣ Da Quing, Finnish Diabetes Prevention, DPP
♣ Once done will likely not be repeated with different dietary intervention
♣ Multiple interventions
Data on food intake patterns:
♣ High carb diets cause diabetes
• Increased intake of total carbs
• Inc intake of refined carbs, esp high fructose corn syrup
• Reduced intake of whole grain products
• Temporally correlated w/ inc prevalence of obesity and diabetes
♣ High fructose corn syrup is going up, and so is diabetes prevalence
♣ But so is prevalence of smokers, age of having kids, room temps, time spent awake, etc.
♣ Worrisome • Correlates doesn’t necessarily mean cause • Inc total E intake, reduced EE • Why are people eating this way? o Food industry/government is making them do it o They’re just dumb o Palatability is the priority • How are we going to impact this?
carbohydrate subtypes
sucrose vs fructose
mixed data
♣ Fructose is not glucose and so doesn’t raise glucose levels
♣ However, has unique metabolic effects on liver
♣ Clearly causes hepatic insulin resistance in rodents independent of weight gain
♣ Growing evidence of adverse effects in humans
♣ Fructose metabolism is diff than glucose in that it bypasses PFK and as a result is rapidly driven down glycolysis in a manner that is less regulated than glucose
♣ Effects of fructose on body fat in humans trial:
• Fructose has a much higher total body fat, and more visceral abdominal fat, than glucose
• Plasma triglyceride levels were higher on fructose too
• Insulin sensitivity changes on high fructose diet
epidemiological studies on Fiber, GI, and GL
issues w/ GI, fiber, whole grains, vegetables
o Inc fiber intake assoc w/ lower insulin levels and less diabetes
o Glycemic load: GI times carbohydrate load
♣ Lower glycemic load is better for you
o Glycemic index down and fiber up seems to be god for you
Issues
o High fat/sucrose/fructose foods have a low GI
o GI information not on labels, fiber is
o Complexity with sugar alcohols, amylose and resistant starch
o GI altered by method of preparation and time of day
long term intervention trials on nutrition
o High carb low calorie diets prevent diabetes
o Gold standard
o Used a range of interventions incl reduced total fat, reduced calories, reduced sat fat, inc fiber, inc physical activity
o Goal standard study of Diabetes Prevention Program:
♣ Best prevention is low fat, calorie restricted diet w/ physical activity
TCA cycle produces
NADH and FADH2
• A 75 yo woman is admitted to the hostpital for suspected stroke. Over 18 hrs it takes to evaluate her she gets no glucose or food. Which is the following is likely to occur?
o Phsophenolpyruvate carboxykinase PEPCK activity inc in liver
48 yo woman w/ T2DM w/ A1C of 9% on metformin is place don sulfonylurea. She gains 20 lbs and develops hypoglycemia. You decide to stop the sulfonylurea and start new med. Which is most likely to reduce blood glucose and most weight loss?
GLP-1 agonist
• Which has highest glycemic index?
o White bread (vs karo syrup, pure sucrose, snickers bar, oatmeal)
• Which is mostly likely cause of low glucose?
o Altered mental status, 20 glucose, inc insulin level and low C-peptide level
o Admin of exogenous insulin
• If a drug that inhibited the movement of electrons from NADH to complex 1 of the electron transport sys was taken by a person, which of the following things would occur?
o Lactate levels would rise
o E is till trapped in NADH, pyruvate backs up, everything backs up
• 6yo child gradually inc abdominal girth. Exam has protuberant abomen, inc liver size. Occasionally fussy if didn’t eat, liver enzymes are elevated. Most likely dx
o de-branching enzyme deficiency
• electron transport system inhibited by
o is inhibited by the accumulation of ATP
• after a high carb meal in nl individual insulin rises. Glut4 transporters move to the cell surface in skeletal muscle. Effect is mediated by:
PI3 Kinase
• Nl person eats high carb meal. What happens?
o PFK1 activity inc because F 2,6 bisphosphate inc because PFK2 activity inc
• Following a high carb meal, the hormone GLP-1 is secreted. Which is an effect of the hormone?
o Enhances glucose-stimulated insulin release
• 47 yo alcoholic M admitted w/ withdrawal symptoms and AMS. Hasn’t been eating well for months. Deficiency in niacin could cause:
o inc lactate production
• woman recovering from abdominal surgery. Hasn’t been given food for 24 hrs. what’s true about liver metabolic state?
o Inc PEPCK activity
• 47 M given anti-malaria meds. Found weak, severe anemia, and hemolysis. Defect in pathway that is involved in prod of:
o ribose sugars
• most accurate way to measure habitual food/E intake in weight stable person is:
o doubly labeled water
• 50 k F has mod level of physical activity consumes 15% protein and 35% fat. Roughly how many g/day carbs consume?
o 187 g
o wants us to remember calories/kg- 30 cal/kg
o how many cal/g of food: 9 cal/g for fat, 4 cal/g for protein and carb
• which of following pathophysiological processes comes first in dev of T2D?
o dev of insulin resistance
• athlete does intense exercise. Plasma EPI rises. Which is most accurate about hormone effects on skeletal muscle?
o Activation of glycogen phosphorylase kinase by phosphorylation
• 24 yo M lost for 4 days w/o food. Which substrates would contribute carbons to glucose that liver is making?
glycerol
• 22 F w/ T1D on NPH and regular insulin 2x.day and poor glucose control w/ high blood sugars ranging up to 300s and freq ions down to 40s. which would be most physiologic insulin tx program?
o Glargine once a day and lispro before meals
• Hexokinase and glucokinase differ most importantly in
o Their Vmax and Km
• 22 F for diabetes management during 1st pregnancy. T1D for past 12 yrs. Risk of T1d developing in child
o higher risk than general pop and risk can be assessed by measuring islet cell autoantibodies in child
• following meal insulin rises. Then as a result
o insulin stim’s Glut4 insertion in muscle cells
• 14 M drinks soda. Biochemical prop of fructose in soda that potentially results in adverse health consequences
bypasses PFK
fatty acids
solubility
diet
extreme sugar intake activates enzyme:
• fat does not dissolve in water- water insoluble, nonpolar; separates the lipids from glucose
• most of fat in diet is triglyceride
o body breaks these down into free fatty acids and free cholesterol
o interconversion between cholesterol and cholesterol ester
o pancreas is secreting lipases to break down triglycerides into 2 FFAs and a monoacylglycerol to absorb fat
acetyl CoA carboxylase
categories of lipids fatty acids triglycerides cholesterol cholesterol ester phospholipids
Fatty acids
♣ Acid COOH, with a C chain (18) saturated fat (no double bonds, all have 2 H’s); nonpolar; doesn’t dissolve in water
• “A little polar”
• If you put saturated fats together- they’re going to crystallize and be solid at room temp
• Discouraged from eating too much saturated fat
♣ Omega-3 fatty acid- double bond 3 back from the end; double bonds give you cis configuration and make it kinked
• Unsaturated fat- liquid at room temp; fats that have double bonds and are kinky
♣ Fatty acids can’t turn into glucose, but glycerol can
Triglycerides ♣ Fatty acid esterified to glycerol • The hydroxyl group goes away • Very nonpolar ♣ 3 fatty acids can be unsaturated, polyunsaturated, etc
cholesterol
♣ flat, planar structure w/ cyclics
♣ precursor for other molecs
• cortisol, testosterone, estrogen, vit d
♣ also present in membranes, causes heart disease, etc
♣ a little polar from the OH group at the end
cholesterol ester
♣ has an esterified fatty acid to cholesterol molec
♣ no charge from the original OH
♣ super non-polar
phospholipids
♣ components of membranes; layers lipids and water
• amphiphathic- polar and nonpolar segments
♣ polar head groups facing out and nonpolar tail facing in
♣ glycerophospholipid: glycerol backbone
• esterify fatty acid on x2- nonpolar tail
• PO4 is the polar head group on the 3rd part of the glycerol
o might have something hooked onto it
♣ most polar (of the ones we’ve talked about)
polarity scale for lipids
o free fatty acids (circulates free), phospholipids (circulates in monolayers of bilayers), free cholesterol, cholesterol ester, triglyceride
lipid synthesis processes (4)
de novo lipogenesis
fatty acid oxidation
ketone synthesis
cholesterol synthesis
de novo lipogenesis process
♣ make fat- fat synthesis; some ways analogous to glycogen synthesis
♣ when you’re overfed, you’ll store the extra when you have enough ATP from the cycle and TCA cycle gets backed up- make fatty acids
♣ take citrate out of TCA- convert it back to acetyl CoA, then make it into malonyl CoA to get to fatty acids
♣ acetyl coA to malonyl via Acetyl CoA carboxylase is the key step in this process*
♣ want to make fat when we’re fed; regulated by insulin (make it happen) and CRR (inhibit it)
♣ maolnyl coa to fatty acids via Fatty acid synthase
♣ if we have glycerol somewhere, we can combine glycerol w/ fatty acids to make triglycerides
• now if you have liver cell, taking glucose from diet and turning it into fat and ship out to adipose tissue by turning it into triglyceride and secreting it as a lipoprotein (VLDL very low density lipoprotein)
• lipoprotein lipase takes triglyceride and puts it into the adipose tissue; stored as triglyceride
acetyl CoA–> malonyl CoA–> FAs –> phospholipids, triglycerides, or acyl carnitine
fatty acid oxidation process
adipose tissue w/ triglyceride
o heading for liver/muscle
o using fat as a fuel (alternative fuel to glucose)
o release triglyceride as a fatty acid when you exercise or fast and try to liberate fat
♣ it’s the first regulated step
♣ hormone sensitive lipase breaks TG into FAs
♣ insulin makes this go down, catecholemines makes it go up
o fatty acid then comes into liver/muscle cell
♣ turn it into fatty acyl CoA to activate it and get it into mito
♣ trying to get E out of the fat; burn it and put it in TCA cycle to get E out of it
♣ fatty acyl CoA goes into mito via carnitine palmitoyl transferase** key regulated step to get it into mito
• this is inhibited by malonyl CoA
• malonyl CoA inhibits CPT1 he said?
♣ Now takes the fatty acid and takes off C’s 2 at a time and make acetyl CoA go to right into the TCA cycle
• This is called beta oxidation- taking 2 C’s at a time and making acetyl CoA
• C’s in the fatty acid can’t go all the way around the cylcle and make glucose because they’re being lost as CO2 x2
ketone synthesis process
o If we fast for a really long time, you can use ketone bodies make from acetyl CoA into ketones to feed brain via HMG-CoA synthase (key step)
o Ketones are an alternative fuel source for brain and to a lesser extent muscle
acetyl CoA–> ketone bodies
cholesterol synthesis process
o Acetyl CoA can also be made into cholesterol through anabolic rxn
o Happens in cytosol
o Key regulated enzyme is HMG CoA reductase (statins inhbit this enzyme)
acetyl CoA–> HMG CoA–> Mevalonate –> cholesterol
fatty acid biosynthesis starting material how is it produced? where does this rxn occur? what's the rate limiting step? how do cells regulate FA synthesis? final products? how do cells utilize final products?
acetyl CoA
via pyruvate (glycolysis, proteins, AAs)
acetyl CoA turns into OAA and citrate in the MITO
leaves mito into cytosol as citrate
♣ ATP can inhibit TCA cycle which can allow citrates to accumulate and cross mito membrane, I think he said
♣ In cytosol, citrate can be converted to OAA again or into acetyl CoA via
♣ OAA can be oxidized back into malate, then pyruvate, then back into mito
♣ Acetyl CoA can turn into malonyl CoA via acetyl CoA carboxylase (rate limiting rxn)
rate limiting step: acetyl CoA –> malignly CoA via acetyl CoA carboxylase ACC
♣ Malonyl CoA will be substrate for fatty acid synthase to make palmitic acid- final product of fatty acid synthesis; 16 C saturated
regulate via ACC
final products: palmitate
palmitate can go to ER or mito for elongation, or exclusively to ER for desaturation
♣ Malonyl CoA will be substrate for fatty acid synthase to make palmitic acid- final product of fatty acid synthesis; 16 C saturated
used in lipid membranes, or triacyl glycerides TAGs
fatty acid basics
o Hydrophobic hydrocarbon chain CH3(CH2)n
o Hydrophilic carboxyl group (ionized at pH 7) COO-
o Consists of hydrophobic hydrocarbon chain w/ terminal carboxyl group
o Longer chain = more insoluble in water
o Usually esterified (ex triacylglycerols)
o Plasma fatty acids are transporterd by serum album
o Structural components of membrane lipids, precursors of the hormone-like prostaglandins
o Can also be conjugated on proteins
o Saturated vs unsaturated fatty acids
♣ Double bonds in unsat FAs are nearly always in cis config- kink at that position
♣ Double bonds dec melting temp
♣ Membrane lipids usually contain long fatty acids (>=16 C’s)
• Presence of double bonds helps maintain membrane fluidity
fatty acid naming
A: C’s numbered starting w/ carboxyl C as C1
• Number before colon = C’s in the chain
• After the colon= numbers and position of double bonds
o Ex. 20:4(5,8,11,14) = arachidonic acid
B: C atoms are numbered beginning w/ 2nd C as alpha, beta, gamma, etc.
• The C AFTER the carboxyl group
♣ C of the terminal methyl group is called the omega carbon regardless of chain length
• The double bonds in a fatty acid can also be counted beginning at the omega end
♣ Omega 3 and omega 6 fatty acids
• Linoleic acid (omega 6) and linolenic acid (omega 3) are 2 dietary essential FAs
o Human cells don’t have enzymes to introduce double bonds between C 9 and the omega end of FAs
o Linoleic acid is precursor of arachidonic acid, the substrate for prostaglandin synthesis
Linolenic acid is precursor of other omega-3 FAs important for growth/dev
fatty acid functions
♣ Major hydrophobic components of all cell membranes
♣ Major storage form of metabolic E, 70-80% of caloric reserve is triacylglycerols
♣ Essential precursors for eicosanoids (paracrine hormones: prostaglandins, leukotrienes, thromboxanes)
fatty acid major sources
♣ Biosynthesis from small molec intermediates derived from metabolic breakdown of sugars, AAs, and fats
♣ Diet essential FAs (linoleic and linolenic acid)
• Linoleic acid: the precursor of arachidonic acid, the substrate for prostaglanding synthsesis)
• Linolenic acid: the precursor of other omega-3 FAs important for growth/dev
fatty acid synthesis
producing the substrates
♣ Occurs when dietary calories are excess
♣ Carbs- glucose – pyruvate- Acetyl CoA + CO2 palmitic acid C16 other fatty acids
♣ Proteins AAs Pyruvate and acetyl CoA (ketogenic AAs) in the above process too
Producing the substrates for FA synthesis
♣ Pyruvate goes into mito membrane; turns into citrate
♣ Citrate then goes out and can become acetyl CoA for FA synthesis
formation of malonyl CoA
conversion of malonyl CoA to FA
synthesis of palmitate by FAs
Formation of malonyl CoA is a rate-limiting step in FA biosynthesis
Acetyl CoA Carboxylase has three functional regions: the Biotin Carrier Protein, Biotin Carboxylase and the Transcarboxylase that transfers the carboxyl group to acetyl CoA to make malonyl CoA. Biotin moves from one active site to the other via a flexible arm.
♣ The mechanism of hormonal regulation is covalent phosphorylation of acetylCoA carboxylase, the rate-limiting step of FA biosynthesis.
♣ Acetyl CoA carboxylase is inhibited by phosphorylation.
♣ Phosphorylated acetylCoA carboxylase can regain partial activity by allosterically binding citrate.
Conversion of malonyl CoA to FA
♣ Malonyl CoA is the substrate for FA synthase (FAS)
♣ FAS (multifunctional enzyme)
• 7 enzyme activities
• acyl carrier protein (ACP)
• performs all the steps to convert malonyl CoA to a FA
♣ the FA molec is synthesized 2 C’s at a time (4 step repeating cycle with the extension of 2 C’s/cycle)
♣ the product of FAS is palmitic acid (16:0)
• palmitate is released from FAS by the palmitoyl thioesterase activity and can then undergo separate elongation and/or desaturation to yield other FA molecs
synthesis of palmitiate by FAS
♣ 4. Condensation to form acetoacyl ACP
♣ 5. Reduction the Keto group to an alcohol
♣ 6. Dehydration to introduce a double bond
♣ 7. Reduction the double bond
♣ ACP: acyl carrier protein
♣ Repeat these steps
♣ 1st 2 c’s will be from acetyl CoA; the rest of the C’s are from malonyl CoA; he wants us to know that
FA elongation and desaturation
♣ elongation of palmitate occurs in mito and ER
♣ a family of enzymes designated fatty acid elongases catalyze the initial condensation step for elongation of saturated or polyunsaturated FAs
♣ formation of double bond in FA involves ER membrane proteins in mammalian cells
• called mixed-function oxidases
♣ mammalian cells are unable to produce double bonds between carbon 9 and the omega-end of the chain
♣ thus some polyunsaturated FAs are dietary essentials, eg linoleic acid
metabolic regulation of FA synthesis
diet and metabolic conditions
long-term regulation by gene transcription
short term
Diet and Metabolic Conditions
• High carbohydrate leads to high pyruvate and acetyl CoA levels in the mitochondrion, which favors production and translocation of citrate from the mitochondrion to the cytosol, thus stimulating fatty acid synthesis.
• High fat/low carbohydrate leads to low pyruvate flux in the mitochondrion. Fat metabolism is associated with elevated acyl CoA in the cytoplasm. Both conditions reduce fatty acid biosynthesis.
• Hormonal environment: high insulin favors lipogenesis (fatty acid biosynthesis); high glucagon favors lipolysis (-oxidation) and decreased fatty acid biosynthesis.
Long-term regulation by gene transcription
• Prolonged consumption of a diet containing excess calories causes an increase in acetyl CoA carboxylase and fatty acid synthase synthesis; in contrast, fasting causes a reduction of acetyl CoA carboxylase and fatty acid synthase.
Short term regulation of fatty acid biosynthesis
♣ citrate
• Availability of cytosolic citrate determines the amount of acetyl CoA available for FA synthesis
• Also helps produce NADPH for reducing equivalents used in the rxns
• citrate can also activate acetyl CoA carboxylase by causing polymerization of the enzyme (conformational change) and increasing Vmax
♣ Palmitoyl CoA
• Acts as inhibitor of Acetyl CoA carboxylase ACC
• Cytosolic levels are elevated during starvation or on high fat diets
♣ insulin and glucagon
• Insulin promotes fatty acid synthesis indirectly by promoting glucose utilization (increases pyruvate flux), directly by dephosphorylation and activation of acetyl CoA carboxylase.
• Glucagon increases intracellular cAMP leading to phosphorylation and inactivation of acetyl CoA carboxylase.
♣ Regulation of Acetyl CoA Carboxylase ACC is the key for regulating fatty acid biosynthesis
TAG
activation of FFAs
storage of fatty acids
Activation of free fatty acids and glycerol for synthesis of TAG
♣ Free FAs must be activated before they can be attached to glycerol 3-phosphate
• Via fatty acyl CoA synthetase
♣ Synthesis of glycerol 3-phsophate
Storage of fatty acids as TAGs
♣ Synthesis of TAG from glycerol 3-phosphate and fatty acyl CoA includes sequential addition of two fatty acids from fatty acyl CoA, then removal of the phosphate to add the third fatty acid.
♣ The fatty acid on carbon 1 is typically saturated, that on carbon 2 is typically unsaturated and that on carbon 3 can be either.
♣ TAGs are the major storage form of fatty acids.
♣ TAGs synthesized in the liver are packaged with cholesteryl esters, cholesterol, phospholipids and apolipoprotein B-100 to from VLDL for delivery to the body.
chronic alcoholism effects on fatty acids
Chronic alcoholism causes hyperlipidemia in both liver and serum
♣ Ethanol is oxidized to acetate, primarily in liver acetyl CoA Fatty acids
♣ Inc NADH/NAD slows TCA cycle and fatty acid oxidation, promotes DHAP glycerol 3-P via NADH
♣ Glycerol 3-P + FAs triacylglycerides
♣ The liver secretes abnormally high levels of VLDLs.
• However, chronic liver dysfunc impairs protein synthesis, incl ApoB-100.
Liver becomes unable to produce and secrete VLDL, increasing hepatic fat buildup
- A healthy 27-year-old woman consumed a breakfast of a large bowl of Coco-puffs (a sugary cereal), 2 pieces of toast, 2 eggs, orange juice and coffee at 7:30 AM. At 11:00 AM, after driving to school and sitting in lecture for 2 hours, she consumed a 32-ounce regular (non-diet) soda. The gene encoding what protein is most likely transcriptionally induced at noon compared to at 6:00 AM in her liver?
- Several hours later, in addition to CO2 where are a large percent of the carbons from the fructose in the soda most likely to be?
• Fatty acid synthase
VLDLs
• Researchers were studying the regulation of hepatic fatty acid synthesis. They were most likely to find that the Vmax of the acetyl CoA carboxylase (ACC) reaction is increased when:
• Insulin signaling stimulates expression of the ACC gene.
galactosemia
signs and symptoms
tx
Signs and Symptoms*:
♣ Early Failure to Thrive (vomiting with milk)
♣ Hepatomegaly/Cirrhosis
♣ Cataracts/Visual Impairment
♣ Mental Retardation
♣ Diagnosis: Non-glucose reducing substance in the urine while on lactose containing diet: breast milk or infant formula
Treatment: Lactose-free diet
♣ N.B.- Galactosemia is part of the Newborn Screening Program in most states
fructose
pathway?
hereditary fructose intolerance
Bypasses PFK-1; enters glycolytic pathway below PFK-1
Hereditary fructose intolerance
♣ Due to deficiency in Aldolase B which splits Fructose 1 P into 3 carbon intermediates that can enter glycolysis.
♣ Effect is accumulation of fructose 1P which has toxic effects on liver, kidney and brain
♣ Symptoms occur with the introduction of fruits and other sources of fructose in the diet in the first year of life (not at birth or in the first few months)
♣ Symptoms: nausea, vomiting, sweating, lethargy, hypoglycemia, hepatomegaly
♣ Increased liver function tests, may progress to severe liver injury. Renal dysfunction may be present
♣ Treatment is avoidance of fructose/sucrose/sorbitol in the diet.
inborn errors of fat metabolism
carnitine problems
♣ L-Carnitine- Primary or dietary
♣ Carnitine Palmitoyl-Transferase (CPT)-I
♣ Carnitine/Acylcarnitine Translocase
♣ Carnitine Palmitoyl-Transferase (CPT)-II
♣ overall Fatty acid oxidation problems***
acetyl CoA dehydrogenase deficiencies
♣ MCAD, LCAD, etc (medium and long chains)
HMG-CoA synthase/Lyase
♣ Appears in ketone production and cholesterol production pathways
dec FA oxidation and ketone formation
♣ Decreased fat oxidation in liver deprives gluconeogenesis of a source of fuel.
♣ Decreased availability of acetyl CoA from fatty acid oxidation and/or ketones makes most tissues obligate glucose utilizers, therefore greatly increasing glucose utilization and predisposing to hypoglycemia.
dec FA oxidation and ketone formation general clinical feats labs newborn screening chains inheritance pattern
♣ Decreased fat oxidation in liver deprives gluconeogenesis of a source of fuel.
♣ Decreased availability of acetyl CoA from fatty acid oxidation and/or ketones makes most tissues obligate glucose utilizers, therefore greatly increasing glucose utilization and predisposing to hypoglycemia.
Common clinical features
• fasting hypoglycemia with low ketones, liver failure, hypotonia.
Lab features
• hypoglycemia, low ketones, coagulopathy hyperammonemia (from excess AAs coming into the TCA cycle for gluconeogenesis), and elevated CK from exercise-induced rhabdomyolysis
• Hypoglycemia
• Abnormal urinary organic acids (W-oxidation)
• Increase in acylCoA derivatives in blood and urine
• Decreased carnitine/Increased acylcarnitines- blood
Newborn screening
• identified a combined incidence of 1:5000 for FAOD. Most are treatable with a good long term outcome.
MCADD
clinical feats
dx
tx
Medium Chain [MCAD]- most common (1:9000) Detected on the Newborn Screening Tests
MCADD
• Enzyme that catalyzes initial setp in B-ox of C10-C6 straight chain acyl-CoAs
Clinical Features:
o Vomiting, lethargy, hypotonia, +/- seizures
o Hypoketotic hypoglycemia
o Hepatomegaly, fatty liver
o May resemble Reye syndrome (acute noninflammatory encephalopathy with hyperammonemia, liver dysfunction)
o Rhabdomyolysis or cardiac symptoms (V fib and cardiac arrest) have been observed
Diagnosis:
o MS/MS-based acylcarnitine analysis of plasma with increased C8 and C8/ C10/carnitine ratio
Treatment:
o Avoid fasting and provide a carb-rich diet
o In those < 1yr of age, uncooked cornstarch may be needed to avoid decompensation during overnight fasts
o Prompt treatment of infections
summary- inborn errors
screening
dx
tx
♣ Newborn screening has been instituted to identify infants before symptoms develop
♣ Definitive diagnosis typically involves
• Measuring precursor that is present in excess.
• Measuring the activity or expression of the enzyme that is likely defective.
♣ Treatment involves making sure they have enough dietary carbohydrate at all times, or avoiding the offending nutrient (the one that cannot be metabolized).
additional important causes of hypoglycemia
other causes
o Counter-regulatory hormones help maintain glucose during periods of fasting
o Insulin should be low or undetectable during fasting
hormone dysregulation Hypopituitarism primary adrenal insufficiency hyperinsulinism inc insulin secretion or admin
others Salicylate intoxication Ethanol intoxication Diarrhea and malnutrition - Decreased substrates for gluconeogenesis Dumping syndrome - Occurs in children with Gtubes and Nissen Ketotic hypoglycemia Disorders of Amino Acid metabolism Maple syrup urine disease Methylmalonic acidemia Tyrosinemia
hormonal dysregulation causing hypoglycemia
Counterregulatory hormone Defects • Hypopituitarism • Growth Hormone Deficiency • ACTH or cortisol deficiency • Beta-blocker (results in lack of epinephrine)
Defects in Insulin Suppression • Congenital Hyperinsulinism • Infant of a diabetic mother • Iatrogenic • Insulinoma
hypopituitarism causing hypoglycemia
deficiency
clinical feats
causes
multiple hormone deficiencies
♣ ACTH and / or GH deficiency
Clinical Features: • Midline defects • Micropenis, undescended testes • Jaundice • nystagmus • Poor growth
Causes: • Septo-optic Dysplasia • “Empty Sella” syndrome • Ectopic Pituitary • Pituitary Tumor or Irradiation • Isolated GHD is not commonly associated with hypoglycemia
primary adrenal insufficiency
clinical features
common causes
Clinical features: • Poor growth/weight gain • Decreased energy • Nausea, vomiting, abdominal pain • Hypotension • Hyperpigmentation • Salt craving • Associated autoimmune diseases
Common causes • Congenital adrenal hyperplasia • Adrenal hemorrhage • Addison disease • Adrenoleukodystrophy
hyperinsulinism neonatal childhood adolescents features in a newborn
Neonatal:
• Infants of Diabetic Mothers: “Transient”
• Congenital hyperinsulinism “permanent”
Childhood:
• Islet Cell Adenoma
• Insulin O.D., Type 1 DM, Child Abuse
Adolescents - as above and:
• Oral Hypoglycemic Agent Ingestion
• Factitious”- hypoglycemic symptoms only
Large for Gestational Age
Glucose Infusion Rate >10mg/kg/min to sustain normoglycemia
Non-ketotic (may see slight ketonuria)
Non-suppressed serum insulin
Rise in blood glucose >40mg/dL after glucagon (reflects increased storage of liver glycogen)
inc insulin secretion or admin
♣ Infants of Diabetic Mothers
♣ Congenital hyperinsulinism (genetic)
♣ Islet Cell Adenomas
♣ Insulin Overdose • Accidental in Type 1DM • Iagtrogenic or munchausen by proxy o Criminal: child abuse, homicide • Ingestion of oral hypoglycemic agents
ketotic hypoglycemia
One of the most common causes of hypoglycemia in childhood Diagnosis of exclusion Lack of substrates for gluconeogenesis Hypoglycemia after fasting 14-24 hours Presents at 1-5 years old Spontaneously remits at 8-9 years old
mitochondrial disorders
13/120 proteins needed for oxidative phosphorylation are coded by mitochondrial DNA
Disorders of mitochondrial function are expressed in tissues with the greatest energy requirements
- Heart
- Skeletal muscle
- Brain and nerves
Myopathies: exercise induced fatigue and muscle breakdown (rhabdomyolysis)
Retinal degeneraton
key to evaluating hypoglycemia
the critical sample!!
CONFIRM BG <50 mg/dl
Plasma bicarbonate, ketones (beta-hydroxybutyrate), insulin, cortisol, growth hormone, free fatty acids, lactate, and pyruvate, (c-peptide, total and free carnitine, acyl carnitine profile)
Urine ketones and organic acids
interpretation of critical labs: hypoglycemia
acidosis:
with high ketones: Normal ketotic hypoglycemia Panhypopituitarism GH deficiency ACTH/cortisol deficiency GSD 3,6,9,10
with high lactate: GSD 0 F-D-Pase deficiency Pyruvate carboxylase deficiency Normal neonates
no acidosis, low ketones:
with low FFAs
Hyperinsulinism
Hypopituitarism
with high FFAs
Fatty acid oxidation disorder
Defect in ketogenesis
glycogenolytic defect
problem with
glycogen –> G6P
Gluconeogenetic defect: Fructose-1,6-bisphosphatase deficiency
problem with
G6P–> Triose 3-P
glycogen storage disease type 1
problem with
G6P –> glucose
fatty acid oxidation disorder
problem with
beta oxidation
fatty acid oxidation: carnitine cycle disorder
problem with
carnation transporter
CTP1 w/ Acetyl-CoA–>acyl-carnitine
translocate w/ acyl-carnitine –> acyl-carnitine
CTP2 w/ actyl-carnitine–> acyl-CoA
galactosemia
problem with
galactose to G1P
hereditary fructose intolerance
problem with
fructose to trips 3P
lipids and CVD risk LDL-C VLDL-TG HDL-C epidemiology biological plausibility clinical trials
LDL-C
Epidemiology +++
Bio plaus +++
clinical trials +++
VLDL-TG
Epidemiology ++
Bio plaus +
clinical trials +/-
HDL-C
Epidemiology ++
Bio plaus ++
clinical trials -
determination of lipoprotein levels
Adults 20 y/o and older should have a fasting lipid panel done at least every 4-6 years
Obtain complete lipoprotein profile after 8-12 hour fast
LDL-C is primary lipoprotein of “interest”
Measure: Total Cholesterol, HDL-C, and triglycerides (TG)
Calculate LDL-C (Friedewald Formula):
In fasted state:
Total-C = LDL-C + HDL-C + VLDL-C
VLDL-C = TG÷5 when TG are <400 mg/dl
Therefore:
LDL-C = Total Cholesterol – (HDL-C + TG/5)
elevated LDL cholesterol associations
Biologic Plausibility
LDL is central in the development and progression of atherosclerosis
LDL-C lowering with statins stabilizes atherosclerotic plaques
Epidemiology
LDL-C elevations are associated with an risk of coronary heart disease
Randomized Trials
LDL-C lowering with statins reduces heart disease related events and deaths
what is nl LDL-C?
Based on population curves:
Average LDL-C in the US is 116 mg/dl
Based on “biology”:
Other mammalian species have LDL-C ~30-50 mg/dl
Hunter gatherer populations have LDL-C ~60-70 mg/dl
We’re born with LDL-C ~30 mg/dl
Based on morbidity:
Majority of CHD occurs with “average” cholesterol
CHD can/does occur with “low” cholesterol levels
Is there a threshold at which point no atherosclerosis occurs?
how to assess atherosclerotic risk
determine the presence of major CHD risk factors
“other” cardiac risk factors
risk estimator
Age, male > female
African American vs. Caucasian
Cigarette smoking - current
Hypertension
Systolic BP >140 mm or on antihypertensive therapy
Higher total cholesterol
Implies higher LDL-C
Low HDL-C
Diabetes
other risk factors
o Life-Habit Risk Factors:: --Metabolic syndrome --Sedentary Lifestyle --Atherogenic Diet --Pyschosocial Factors o strong family history o emerging risk factors inc apo B inc LDL particle # inc lipoprotein (a) inc homocysteine Subclinical atherosclerosis
risk estimator Race Gender Age Total cholesterol HDL cholesterol Blood pressure / Use of BP medicines Diabetes status Smoking status
pathophysiology of dyslipidemia
inc production of lipoproteins
and/or
dec catabolism of lipoproteins
assessing acquired causes of dyslipidemia
Lifestyle
Diet, inactivity, alcohol
Medications (steroids)
Diabetes/Glucose intolerance: glucose, HbA1C***
Thyroid disease: TSH***
Liver disease: liver function tests***
Kidney disease: creatinine, urine protein***
familial hypercholesterolemia FH
Most often a defect in the LDL receptor*
A decrease in LDL removal
~50% receptor-negative
~50% are receptor-defective
Autosomal dominant Gene frequency: 1 in 250-300 Partial (heterozygote): LDL-C 200-300 mg/dl Complete (homozygote) absence of the LDL receptor: LDL-C >500 mg/dl
Premature death from atherosclerosis
occurring frequently before age twenty in homozygotes
cell biology of the LDL receptor
PCSK9
LDL binds to LDL receptor, endocytosed into a clathrin-coated vesicle, moves into lysosome, and LDL receptor is recycled
PCSK9-mediated degradation of the LDL receptor- a GOF mutation will result in too much degradation, and hypercholesterolemia because it’s not being endocytosed by the liver
Marcus corneas
xanthelasmas
tendinous xanthomas
marcus corneas:
lipid deposits at the limbs of the cornea
may reflect hypercholesterolemia, or may be a nl variant
more common as people age
xanthelasmas:
Lipid deposits in the skin of the eyelid. May reflect
hypercholesterolemia, or may be a normal variant.
tendinous xanthomas:
Typically involves the Achilles tendons and extensor tendons of the hands. Indicative of familial hypercholesterolemia.** specific
hypertriglyceridemia
biologic plausibility
epidemiology
randomized trials
May promote clotting, may promote vascular endothelial dysfunction, may be directly delivering cholesterol to the vessel wall.
Epidemiology
Hypertriglyceridemia in the setting of metabolic syndrome, type 2 diabetes (especially in women) has been shown to be associated with CVD risk
Severe hypertriglyceridemia is associated with pancreatitis
Randomized Trials
Triglyceride lowering has not been shown to independently reduce CVD related events and deaths
hypertriglyceridemia evaluation acquired causes of hypertriglyceridemia genetics severe clinical feats familial goals
NCEP/ATP III Classification of Triglycerides Normal: <150 mg/dl Borderline High: 150-199 mg/dl High: 200-499 mg/dl Very High: 500 mg/dl
causes: behavioral -ethanol, high fat/sugar intake, sedentary lifestyle altered physiology meds (esp oral contraceptives)
genetics
There are no single genes that explain hypertriglyceridemia.
A number of SNPs on known and unknown genes have been identified
LPL and apo A5 most relevant
severe clinical feats Eruptive xanthomata Lipemia retinalis (white vessels in eye) Hepatosplenomegaly Abdominal pain +/- acute pancreatitis 5% fatality
familial LPL deficiency (rare) Apo CII deficiency GPIHBP1 deficiency -doesn't req secondary disorder pancreatitis risk no premature CHD eruptive xanthoma lipemia retinalis
goals
Severe Hypertriglyceridemia (>500 mg/dl)
Primary goal is to prevent pancreatitis
Goal is to clear chylomicrons - reduce TG <500 mg/dl
Moderate Hypertriglyceridemia:
Primary aim of therapy is to focus on lifestyle/statin recommendations.
Further treatments need more evidence.
familial dysbetalipoproteininemia
“Broad Beta Disease”
Manifest as inc cholesterol and inc TG
Autosomal recessive disorder
Apo E2 rather than E3 and E4
Results in chylomicron remnant and IDL accumulation
Increased risk for premature CHD
Diagnosis: Lipoprotein electrophoresis, apo E genotype (Alzheimer’s predisposition)
presentation
planar, palmar, and tuboeruptive xanthomas
-extensor surfaces of arms/legs/palms. rare, but indicative of broad beta or remnant disease
low HDL-C
bio plausibility
epidemiology
randomized trials
Biologic Plausibility
Reverse cholesterol transport
Anti-oxidant and anti-inflammatory effects
Epidemiology
Clear association between low HDL-C and increased risk for CVD in many but not all populations.
Randomized Trials
HDL-C raising has not been clearly shown to reduce CVD related events and deaths
Severe HDL deficiency genes Tangier's disease acquired causes tx goals
ABC is ATP Binding Cassette gene family- relates to reverse cholesterol transport transmembrane proteins transport ligands amino acids nucleotides lipids
ABCA1 gene is altered in Tangier disease and familial hypoalphalipoproteinemia
Tangier disease- enlarged orange tonsils from accumulation of cholesterol. inc risk of TAD (rare, but telling?)
acquired causes of low HDL-C -Diet: High carbohydrate Obesity -Drugs: β-blockers Diuretics Sex steroids – progestins, androgens HIV protease inhibitors -Others: Hypertriglyceridemic disorders Lifestyle – sedentary, smoking
tx goals (<40 mg/dL)
First reach LDL-C goal, then:
-Intensify weight management and increase physical activity
-If TG >200 mg/dL, consider drug treatment of TG
-Presently, HDL raising drugs are not indicated
High levels of LP little “a” correlate w/ inc CHD risk
dietary pattern recommendations for LDL-C and BP lowering
Advise adults who would benefit from LDL-C or BP lowering to:
Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains: includes low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils and nuts; and limits intake of sweets, sugar-sweetened beverages and red meats.
Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for other medical conditions.
Recommended dietary patterns include DASH, USDA, AHA, Mediterranean
lowering LDL-C statins MOA 6% rule downsides
with statins: benefit on major CVD events and CVD deaths
high intensity:
atorvastatin (40 and 80mg; generic)
Tosuvastatin (20 and 40mg; generic)
moderate intensity: Atorvastatin Tosuvastatin Sinvastatin Pravastatin Lovastatin Fluvastatin
low intensity:
rarely used, except in statin intolerant pts
Pravastatin
Lovastatin
MOA
HMG CoA reductase inhibition
Decrease hepatic pool of free cholesterol
Increase expression of LDL receptors on cell membranes
Increase catabolism of VLDL and LDL
Decrease LDL-C concentrations
6% rule!!
w/ each statin dose doubling, LDL-C falls by 6%
downside of statins:
abnl AST and ALT (rare)
myopathy: any disease of muscles, esp myalgias* but very rarely rhabdomyolysis
cognitive impairment (rare)
new onset of T2DM (pertinent- 10% inc risk)
other mech’s to lower LDL-C
plant stanols
ezetimibe
BAS
plant stanols Inhibition of cholesterol absorption may interfere w/ abs of lipid-soluble vitamins low abs, dose 2-3g/day reduce LDL by 5-10%
Ezetimibe
Selective cholesterol absorption inhibitors (block Cl abs at intestinal brush border)
reduces intrahepatic cholesterol pool size
NO side effects
BAS (bile acid sequestrates) or resins
Cholestyramine
Colestipol
Colesevelam
Not abs, not metabolized
- Inhibit reabsorption of bile acids
- Decreased reabsorption of bile acids stimulates increased conversion of cholesterol to bile acids
-Reduced cholesterol content of hepatic cells
1- Stimulates increased cholesterol synthesis
2- Stimulates LDL receptor synthesis and LDL uptake by the liver**
side effects mouth sensation bloating nausea constipation anal irritation
inhibits Rx abs Digoxin Warfarin Thiazide diuretics Beta blockers Thyroid hormone
Contraindications
Dysbetalipoproteinemia
Elevated TG (>300 mg/dL)
PCSK9 inhibitors-
who?
adverse rxns
been approved in past 4 months
Alirocumab and Evolocumab
to tx adults w/ FH or clinical CAD, who require additional LDL lowering
adverse effects injection site rxns- 5% drug-induced Abs <5% allergy neurocognitive events?
management of very high LDL-C
Maximally tolerated statin + ezetimibe + resin + fenofibrate + niacin
If >200 mg/dL on maximum therapy one of two newly approved drugs and/or LDL apheresis.:
Mipomersen: targeting Apo B at point of synthesis and secretion
MTP inhibition w/ Lomitapide: MOA
acts on liver, intestine, and apoB-48 secretion
need to lower fat intake otherwise lots of steatorrhea
LDL aphaeresis: takes LDL and cholesterol way down, but it will be back up to baseline by 2 weeks
lowering triglycerides in pts w/ hypertriglyceridemia
fibrates- 20-40% omega-3 fatty acids: 15-35% nicotinic acid: 15-35% statins: 0-35% LOW END- MINIMAL OR NO EFFECT high end: mod to high dose
fibrates
clinical evidence
adverse rxns
clinical evidence
Reduce CVD events in high risk patients not treated with statins
Middle-aged men with a non-HDL-C >200 mg/dL
Men with CHD and a low plasma HDL-C (32 mg/dL)
Relevance now in statin era?
Reduction in CVD events in several trials in patients (± statins) with plasma TG >200 mg/dL and low levels of HDL-C
adverse rxns
fenofibrate skin rash myopathy inc LFTs- rare inc Cr- reversible after drug cessation
Gemfibrozil
cholelithiasis
myopathy
GI distress
both are contraindicated in severe hepatic and renal disease
omega-3 fatty acids (fish oil)
fish oil AKA Eicosapentaenoic acid EPA and docoosahexaenoic acid DHA
polyunsaturated
found naturally in marine sources
alpha-linolenic acid (precursor) can’t be synthesized by humans and is found in walnuts and flaxseed, soybean, and canola oils
MOA dec hepatic triglyceride prod and therefore VLDL-TG secretion 3/4 g/day: dec TG 15-35% inc HDL 5-10% none-inc LDL
adverse effect: fishy odor and aftertaste (freezing helps)
indicated: fasting TG >500
nicotinic acid
Nicotinic acid = niacin
adipose tissue:
binds to inhibitory receptor that inc Gi
dec lipolysis (transient effect only)
liver: inc AMP kinase inc FFA oxidation dec TG synthesis dec VLDL synthesis and thus, LDL formation
lipoprotein effects:
inc HDL 10-30%
dec TG 15-35%
dec LDL 5-25%
contraindications
Severe skin rash (flushing in most patients)
Liver disease – moderate to severe
Hyperuricemia and/or gout
Active peptic ulcer or inflammatory bowel disease
Impaired glucose tolerance (relative contraindication)
effects of drugs on HDL levels
therapies
Niacin 15-35% Fibrates 5-15% Statins 5-10% Resins 5-10% Estrogens – p.o. 10-15% CETP inhibitors 40-200%
no evidence, and treating low levels of HDL-C is not a drug indication
heart healthy HDL raising therapies exercise sustained weight loss alcohol smoking cessation
fed state where does glucose go
fed state
most inborn errors don’t relate to the fed state
when eat glucose, it goes to liver, can go through glycolysis, glycogen, HMP pathway, we can get glycerol out of there
if we eat a lot of glucose, we can go through Acetyl CoA and make FFAs and make triglycerides
adipose- can take up glucose and make fat stored as triglyceride
brain- just takes up glucose to keep constant glucose and use it as an oxidative fuel
skeletal muscle- serves as cupboard for glucose- can burn it, or store it as glycogen
fasted state
keep feeding brain- glucose or ketone as an alt
deliver nutrients to liver so we can make glucose for brain
2 glucose relieving pathways from liver:
glycogenolysis when counter regulatory hormones are high
via glycogen phosphorylase is a quick E source shortly after meal
gluconeogenesis fro pyruvate as fast goes on longer
carbons can come into pyruvate as lactate, AA (alanine), AAs entering in the TCA cycle, glycerol from fat breakdown
lipolysis breaks down TGs to give you FFAs to go through beta oxidation to give you acetyl CoA to generate ATP from TCA cycle to generate gluconeogenesis
if fast goes on long enough and we have lots of Acetyl CoA it can also be generated to ketones which is an alt fuel for skeletal muscles
fat can go to muscle so muscle doesn’t have to use glucose so glucose can be preserved for the brain to use (brain can use ketones eventually if you end up in a starved state)
cori gives us substrates for gluconeogenesis
in muscle, you can’t take glycogen and get it out as glucose, but you can take it out as lactate and convert it to glucose in the liver
-can also do this in RBCs
definition of hypoglycemia
Whipple’s triad
lab definition (adults/neonates)
symptoms
Whipple’s Triad: classic symptoms (discussed below)-> BG < 50 mg/dl -> resolution with glucose ingestion
Laboratory definition Adults: plasma venous sample <50s mg/dl (after 84 hrs fasting) Children: 53 (after 30 hrs fasting) In neonates, controversial Term within first 12 hrs: BG <30 After 12hrs: BG <45 After 48hrs: BG <50
symptoms autonomic NS activation: Sweating Shaky, trembling Tachycardia Anxiety Weakness Hunger Nausea/vomiting
Neuroglycopenic symptoms: (looks drunk) Irritable, restless Headache Confusion Visual changes Slurred speech/concentration Behavior changes Somnolence Coma/seizures
hypoglycemia importance
important to ID and tx
Brain relies on glucose (major fuel), ketones, and lactate
In infancy and childhood, hypoglycemia can injure the developing brain and result in permanent neurodevelopmental problems
glucose homeostasis during fasting
first abs
then glycogenolysis
then gluconeogenesis
then fatty acid oxidation
hypoglycemia and timing <4-6 hrs >6-8 hrs >10-12 hrs >12-24 hrs
< 4 – 6 hours: Glucose 6 phosphatase deficiency Milder Glycogen Storage Diseases in infants and children Hyperinsulinism Cortisol and GH deficiency in infants
> 6-8 hours:
Cortisol deficiency and fatty acid oxidation disorders in infants
Milder glycogen storage and gluconeogenic diseases
Cortisol and GH deficiency in children and adults
> 10-12 hours:
Fatty acid oxidation disorders in older children and adults
Mild disorders of GSD in adults
> 12- 24 hours:
ketotic hypoglycemia (not enzyme defect, but common)
Fatty acid oxidation disorders in older children and adults
inborn errors of carbohydrate and fat metabolism
presentation
ppt factors
fat oxidation vs glucose disorders
Many present as hypoglycemia (<50 mg/dl)
May present with accumulation of abnormal amounts of substrate behind block: glycogen, galactose, fructose, lactate, triglycerides
Precipitating factors: fasting, illness, exercise, ingestion of dietary galactose or fructose
Presence of ketones separates defects in fat oxidation from glucose disorders
inborn errors of carb metabolism
Glycogen storage diseases
Glycogen synthase, branching enzyme
Glycogen phosphorylase, phosphorylase kinase
Gluconeogenic Defect: F1,6 bisphosphatase deficiency
Glucose 6 phosphatase deficiency
Hereditary Fructose Intolerance
Galactosemia
glycogen storage diseases
Disorder of glucose release
Disorders of synthesis
Disorders of degradation
glucose-6-phosphatase deficiency define impairment signs and lab findings tx
(GSD-I Von Gierke)
Deficiency of glucose-6-phosphatase: the final common pathway: impairment in glucose release from the liver from glycogenolysis and gluconeogenesis
Signs and Laboratory Findings: Hepatomegaly (pronounced) Hypoglycemia: early (<4h) and severe Lactic acidosis Hypertriglyceridemia and hypercholesterolemia Hyperuricemia Short stature, doll-like face
tx Constant glucose supply! Frequent feeding Nasogastric drip feeding Uncooked cornstarch: Slow release CHO, lasts 6 h, slow start
Any possible hypoglycemia needs prompt iv glucose treatment
Results: Normalization of growth Maintaining glucose > need for gluconeogenesis Decrease cholesterol and triglycerides Still hepatomegaly but less pronounced
disorders of glycogen synthesis
Glycogen Synthase deficiency (GSD 0)
Branching (1,4—1,6) Enzyme deficiency
Glycogen Synthase deficiency (GSD 0)
Clinical presentation: hyperglycemia after a meal, followed by low blood sugar later, increased lactate, and severe ketotic hypoglycemia
No liver enlargement unlike other GSDs
Treatment: high protein diet to provide gluconeogenesis substrates and low glycemic index complex carbs to minimize post-prandial hyperglycemia and hyperlactacidemia
Branching (1,4—1,6) Enzyme deficiency
Abnormal glycogen: associated with tissue damage
Symptoms: Progressive liver cirrhosis (transplant by age 4 – 6 YRS) Hepatosplenomegaly, failure to thrive Nonprogressive form: mild mutations Cardiomyopathy Muscle: Neonatal severe hypotonia and muscle weakness Childhood muscle weakness Neuropathy
Diagnosis: pathology on muscle biopsy, enzyme assay in liver or fibroblasts, mutation analysis
Prognosis: mutation analysis can aid
Treatment: supportive
disorders of glycogen breakdown
Glycogen Phosphorylase (GSD VI)
Glycogen Phosphorylase kinase (GSD IX)
Debranching Enzyme (GSD III)Deficiencies in:
Glycogen Phosphorylase (GSD VI)
Glycogen Phosphorylase kinase (GSD IX)
Debranching Enzyme (GSD III) debranching enzyme: α-1,6-glucosidase GSD-IIIA: deficiency in liver and muscle (85%) GSD-IIIB: deficiency in liver only (15%)
Initial presentation:
Similar to GSD-I: hypoglycemia, hepatomegaly, growth retardation, mildly elevated cholesterol
lactate and uric acid normal
Elevation of liver enzymes, fasting ketosis
Late presentation:
Cardiomyopathy
Myopathy (3-4th decade)
Polyneuropathy
Cirrhosis
Abnormal glycogen causes tissue
(Liver, heart, muscle) damage
Treatment:
Continuous glucose, raw cornstarch, to keep BG >70
High protein diet may help myopathy and growth failure
gluconeogenic enzyme deficiencies
Pyruvate Carboxylase and PEP Carboxykinase: rare- probably lethal
Fructose-1,6-bisPO4ase deficiency
Hypoglycemia: late and mild
Metabolic acidosis: severe lactic acidosis
Normal lactate/pyruvate ratio
Often acidosis with Kussmaul breathing primary symptom
Ketones present and appropriate
Mildly elevated liver enzymes, no ammonia
TREATMENT:
Acute: give glucose -> will correct lactate
Give bicarbonate sparingly, acidosis corrects with glucose
Prevention: avoid long fasting, uncooked cornstarch at night
Prompt treatment of hypoglycemia
hereditary fructose intolerance cause effect symptoms tx
Due to deficiency in Aldolase B which splits Fructose 1 P into 3 carbon intermediates that can enter glycolysis.
Effect is accumulation of fructose 1P which has toxic effects on liver, kidney and brain
Symptoms occur with the introduction of fruits and other sources of fructose in the diet in the first year of life (not at birth or in the first few months)
Symptoms: nausea, vomiting, sweating, lethargy, hypoglycemia, hepatomegaly
Increased liver function tests, may progress to severe liver injury. Renal dysfunction may be present
Treatment is avoidance of fructose/sucrose/sorbitol in the diet.
diet calcs
total E= how many calories you get to eat (related to lean/total body mass)
-some % of fat, carb, and protein
total E= 25-35 kcal/kg; simply remember 30kcal/kg body weight
ex 50kg woman= 1500cal/day
30% fat = 450 cal
9 cal/g fat = 50g fat per day
50% carb = 750 cal
4 cal/g carb = 187.5g carbs per day
20% protein = 300 cal
4 cal/g protein = 75g protein per day
fat overview
saturated fat- no double bonds
stack on e/o easily; solid at room temp
unsaturated- double bonds
cis bonds typically
omega 6 and 3 are essential fatty acids
trans fat- a trans double bond
“partially hydrogenated” modified by food industry
(no kinks)- solid at room temp
-don’t have enzymes to handle these well; bad for pts
American diet
33-37% fat
50% of fat is sat
15% protein- mostly animal
48-52% carbs- almost 1/3 from simple sugars
BIGGEST changes in modern diet: inc omega-6 fat (corn oil) trans fat reduced whole grains and fiber inc total E intake (calories), no fasting
it’s more what type of fat you eat than how much fat you eat
-probably want more monounsat fat (olive, canola) than polyunsat (sunflower, corn)
health effects of high fat diets
cholesterol
gold standard data
high fat often means high calorie diets- E dense
observational studies- suggest all fats aren’t equal
- type of fat, vs amount of fat
- sat fats and trans fats are probably worse for you- higher risk of CAD
- omega 3 and omega 6 FAs appear to lessen risk for CAD
higher cholesterol levels also gives you higher CAD risk
-but DIETARY cholesterol doesn’t really affect plasma cholesterol
gold standard data- long term, randomized clinical trials in humans
fish and/or omega-3 fatty acids
plant sterols
fish/omega-3 fatty acids
although controversial, evidence for dec:
sudden death
arrhythmias
triglycerides
thrombosis
coronary morbidity and mortality in pts w/ CHD
plant sterols
structurally similar to cholesterol but isolated from plant fats
made commercially into margarine-like products
inhabit cholesterol abs from the intestine
1-3g/day lowers LDL cholesterol
low carb and low fat diets
summary of weight effects
low carb vs low fat diet:
no difference in weight loss at 2 yrs
both reasonable diets for weight loss
low carb diet may help you lose more weight, but low fat diet may help you lose more fat mass
diff in weight, but essentially no diff in fat loss
the best predictor of weight loss is compliance!!
diet composition doesn’t matter much for weight loss
no advantage to low carb diets
adherence w/ tx plan is most important
low carb and mediterranean diet are reasonable options, may be better in some
which diet features may predispose to diabetes
high fat diets w/ insulin
gold standard
total calories, positive E balance- most important thing Bessessen thinks
- – weight gain!! and obesity
- reversing pos E balance has strong protective effect
relative amounts of fat or carbs; types of fat play secondary role, Bessesen thinks
high fat diets- cause insulin resistance worse w/ saturated fats omega 6's almost as bad monounsat's and fish oils may be neutral or beneficial
“gold standard” approach is low fat diet w/ modest caloric restriction, although Mediterranean diet might be alternative
