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
