Diabetes(Pharmacology(
Drug(Types!(
Sulfonylureas(
(Insulin(secretagogues)(
Glyburide!
Glipizide!
Glimepiride!
Mechanism(
Biguanides((Metformin)(
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GLPT1(Agonists(
Exenatide!!
Liraglutide!
Exenatide!Qwk!
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DPPT4(Inhibitors!
Sitagliptin!
Saxagliptin!
Linagliptin!
Amylin(
Pramlintide!
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SGLUT2(Inhibitor(
Canagliflozin/Invokana!
Lifestyle(Change(
Kinetics(
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Oral!agent!(1!or!2x/day)!
Duration:!glyburide>glimepiride>glipizide!
Hepatic!metab;!renal!excretion!
Side(Effects/Adverse(
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Thiazolidinediones((TZDs)(
Pioglitazone!
Rosiglitazone!
Bind!sulfonyl!urea!receptor!!causes!K+!channel!to!close!
!depolarization!Ca!influx!!release(of(insulin!(
Inexpensive!($4/month);!combo!pill!available!with!
metformin,!thiazolidinediones(
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Weight(gain(
Hypoglycemia(
Loses!effectiveness!with!longer!duration!of!diabetes!
(tolerance)!
Can’t(use(if(have(sulfa(allergy(or(G6PD(deficiency(
(will(cause(hemolytic(anemia)(
Risk!of!lactic!acidosis!IF!also!have!contraindication:!
contrast!media,!CHF,!renal!insufficiency,!liver!
disease,!metabolic!acidosis!
GI:(N/V,(diarrhea,(bloating(
Hospitalized!patients!(for!any!reason)!should!stop!
Metformin!until!they!improve/stabilize!
Potentiates!suppressive(effect(of(insulin(on(hepatic(
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Oral!agent!
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glucose(production!!
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Start!at!smallest!dose!and!uptitrate!to!
Does!NOT!stimulate!insulin!secretion!or!increase!
decrease!GI!side!effects!
circulating!insulin!
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Renally!excreted!

Inexpensive!($4/month);!especially!effective!for!insulin!

resistance!
No(hypoglycemia,(no(weight(gain;!can!combine!with!
other!drugs!
Ligands!for!PPARWgamma!receptor!to!stimulate!
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Oral!agent!(1!or!2x/day)!
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Worsening(of(CHF,!fluid!retention,!hemodilution!
adiponectin,!which!increase(insulin(sensitivity!
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Slow!onset!(~1!month)!
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Risk!of!bladder!cancer!with!>1yr!of!pioglitazone!
May!be!beneficial!for!lipids!and!CV!health(BUT(don’t(use( 
Hepatic!metab;!partial!renal!excretion!
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Rosiglitazone(severely(restricted(due(to(adverse(
due(to(cardiacside(effects!
CV(effects(
Expensive!
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Weight(gain(
GLPW1!itself!is!not!an!effective!drug!(too!rapidly!broken!
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Subcut(injection((
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Side!effects!(mostly!nausea)(
down!by!DPPW4)!!why!agonists!were!developed!
!
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Increased!risk!of!pancreatitis?!Inconclusive!data(
Potentiate(insulin(secretion(ONLY(IF(blood(glucose(is(
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Long!acting!Exenatide!Qwk!has!black!box!warning!for!
elevated(
development!of!medullary!thyroid!carcinoma(
Many!effects:!decreases!hepatic!glucose!output,!suppress!
postprandial!glucagon!secretion,!slow!gastric!emptying,!
increases!satiety!
Weight(loss;!expensive!($600/month)!
May!promote!betaWcell!neogenesis,!proliferation!
Aside:'Endogenous'incretins'include'GLP41'(ilieum;'L'cells)'
and'GIP'(duodenum,'K'cells)'
Aside:'incretin'effect'is'diminished'in'Type'2'DM;'also'
glucagon'is'not'appropriately'suppressed'in'the'fasting'
state!
Prevent(breakdown(of(GLPT1!for!24!hrs!
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Oral!(1x/day)!
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Nasopharyngitis;(headache(
Lowers!postprandial!glucose!(multiple!mechanisms)!
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Risk!for!StevenWJohnson’s!Syndrome,!severe!allergic!
Little(effect(on(weight;(less(potent(than(GLPT1(agonist!
reaction!
(DON’T!affect!gastric!emptying!or!satiety)!
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Increased!risk!of!pancreatitis?!Inconclusive!data!
Combo!pill!with!metformin;!expensive!
Amylin=second!peptide!secreted!by!betaWcells;!has!
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Subcut(injection(
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GI:!Nausea,!vomiting!
diurnal!pattern(similar(to(insulin!
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Can’t(mix(in(syringe(with(insulins!
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Can!get!insulinWinduced!hypoglycemia!when!given!
Suppresses(postprandial(glucagon;!slows!gastric!
with!insulin!
emptying;!increases!satiety!
Expensive!($300/month);!only!works!if!already!taking!
insulin!
Aside:'T1DM'have'absolute'deficiency'in'amylin;'T2DM'
have'progressively'decreased'amylin!
Block(SGLUT2!to!prevent!filtered!glucose!from!being!
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Oral!agent!(1/day)!
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Increased(risk(for(UTI(and(GU(infections(
reabsorbed!in!nephron!!excrete(glucose!
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Hepatic!metabolism!
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Increased!risk!for!hyponatremia,!hypovolemia!
Weight(loss,!lowers!BP,!may!improve!betaWcell!fxn!
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Contraindicated!in!renal!disease!
Expensive!
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Brand!new!(2013)!!is!it!safe!long!term?!
Less(calorie!dense!foods,!smaller!portions;!Physical(activity;!Weight(loss!(losing!5W10%!of!total!body!weight=decreased!risk!of!complications)!
Insulin(
RapidTacting((
“"log”'drugs'
Humalog!(Lispro)!
Novolog!(Aspart)!
Glulisine!(Apidra)!
ShortTActing(
“"lin'R”'drugs'
HumulinWR!
NovolinWR!
IntermediateT
Acting((NPH)(
“"lin'N”'drugs'
Humulin!N!
Novolin!N!
LongTActing!
Glargine!(Lantus)!
Detemir!(Levemir)!
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Injected!right!before!a!meal!to!prevent!postWprandial!hyperglycemia!
Used!for!continuous!infusion!pumps!
Can!mix!with!NPH!
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Onset!in!5T15(min!
Peak(1T1.5(hr(
Lasts(3T5(hrs(
Subcut!injection!or!insulin!pump!
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Recombinant!human!insulin!(soluble!crystalline!zinc!!Zn!improves!stability/shelfW
life)!
Inject!30!min!before!eating!
Usually!used!in!hospital(setting!for!DKA!(IV(infusion!of!insulin)!
!
Usually!for!basal!coverage!(2+!times/day)!
Cloudy!(other!insulins!are!clear)!!have!to!mix!before!admin!
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Onset(in(30T60(min((
Peak!in!2!hrs!
Lasts!6W8!hrs!
Subcut!injection,!IV!infusion!
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Onset!of!action(2T4(hrs!
Peak!6W7!hrs!
Lasts!10W20!hrs!
Subcut!injection!only!(2x/day)!
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Cannot(be(mixed(in(same(syringe(with(any(other(insulins((because!of!acidic!pH)!
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Onset!in!1T3(hr!
No(pronounced(peak(
Lasts!24!hr!(glargine)!or!17!hr!(detemir)!
Subcut!injection!only!!
Subcut!injection!!
Rapid!onset!right!before!meal,!with!longer!
lasting!basal!insulin!
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Overadministration!or!
admin!without!
sufficient!carb!ingestion!
can!lead!to!
hypoglycemia(
Biphasic/Mixed(
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Reduce!number!of!injections;!get!basal!and!prandial!insulin!at!same!time(
NPH/Regular!
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NPH/Regular((70/30!or!50/50!mixes!injected!before!breakfast!and!before!dinner(
Intermediate/Hum 
Intermediate/Humalog(or(Novolog((admin!before!eating(
alog!or!Novolog!
Insulin:(Overview(and(Treatment(Strategy(
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Normal!Insulin!
• Pancreas!secretes!about!30!units!of!insulin!per!day!(basal!insulin!plus!insulin!release!in!response!to!exogenous!stimuli!i.e.!blood!glucose!>!100)!
• Prandial!(postWeating)!insulin!has!two(phases:1)!first!phase!(immediate)!and!2)!second!phase!(8W10!min!after!ingestion)!!insulin!concentrations!peak!at!30W45!min!after!ingestion!
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Type(I(Diabetes(Regimen(
• “Basal(bolus”(therapy:!LongWacting!(i.e.!glargine)!injected!once!per!day!+!rapidWinsulin!right!before!meal!(calculate!carbs)!
• Continuous(subcutaneous(insulin(infusion!(insulin!pump):!rapidTacting(insulin(

Advantages:!eliminates!multiple!injections,!can!set!different!basal!rates,!can!have!partial!unit,!can!give!different!bolus!types!
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Disadvantages:!upfront!cost,!significant!training,!motivation,!ability!to!troubleshoot,!interruption!of!infusion!or!“bad!site”!can!lead!to!DKA!within!hrs!
• Considerations(in(choosing(regimen:!age,!duration!of!DM,!complications,!motivation,!activity!level,!daily!schedule!
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When(to(use(insulin(in(Type(2(Diabetes?((
• If!have!contraindications!to!other!agents!(i.e.!renal!or!hepatic!dysfunction,!CHF)!
• If!lifestyle!plus!nonWinsulin!medications!have!not!resulted!in!sufficient!decrease!in!HbA1c!(usually!occurs!10!years!after!onset!of!disease)!
• ALWAYS(use(insulin(if(have(signs(of(severe(insulin(deficiency!!fasting!glucose!>250!mg/dL;!random!glucose!>!300!mg/dL;!HbA1c(>(10%;!hospital!admission!(i.e.!for!DKA,!
hyperglycemic!hyperosmolar!stateWHHS)!
• Usually!add!a!basal!insulin!to!oral!agents!initially!(then!add!rapidWacting!insulins!at!mealtimes!OR!preWmixed!insulin!2x/day!if!necessary)!
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Insulin(Therapy(Targets:((
• Fasting(Glucose:(70T130(mg/dl(
• 2(hr(post(prandial(<180(mg/dl(
• A1c(<7((Many!different!factors!(i.e.!age,!newly!diagnosed,!presence!of!complications,!etc)!influence!whether!you!will!have!a!stringent!(<6.5!HbA1c)!or!lenient!(<8)!goal(
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What(if(the(patient(has(early(morning(HYPERglycemia?!Usually!due!to!1)!inadequate!basal!insulin!or!2)!waning!effect!of!basal!insulin!or!3)!Somogyi!effect!(nocturnal!HYPOglycemia!causes!
surge!of!counterWregulatory!hormones!in!the!morning)!
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Insulin(in(Inpatient(Settings(
• Hyperglycemia!can!occur!for!a!variety!of!reasons!(stress,!medications,!etc)!in!hospitalized!patients!and!is!associated!with!significant!adverse!outcomes!
• Stop(all(oral(agents(and(administer(insulin(for(hyperglycemia!to!reach!targets!of!random!BG<180!mg/dL!and/or!premeal!BG<140!mg/dL!
• Administer!0.5!units!insulin/kg!(half!is!should!be!basal,!half!is!bolus)!!if!under!stress,!you!need!more!insulin!BUT!be!cautious!!!Avoid!hypoglycemia!!
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Barriers(to(insulin(therapy:!fear!of!injections,!hypoglycemia,!gaining!weight,!stigma,!inconvenience!
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Adjusting(insulin:!eliminate(the(lows!first(and!then!eliminate!the!highs;!adjust!dose!10W20%!
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Monitoring(blood(sugar:!glucometers!!check!at(least(2x(per(day!(fasting,!preWlunch,!preWdinner,!bedtime)!and!record!values!!now!have!continuous!glucometers,!but!still!delayed!~15!min!
NOTES(

Glucose!control!decreases!microvascular!mortality!and!complications!!“legacy!effect”!which!means!that!even!if!glycemic!control!got!worse!after!the!study,!morbidity/mortality!was!still!reduced(
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How!do!you!choose!and!combine!therapies?!Consider!MOA,!effectiveness,!side!effects,!cost,!convenience,!nonWglycemic!beneficial!effects,!stage!of!DM,!patient!preference,!baseline!condition(
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DM2!Treatment:!Metformin(is(firstTline(
• Weight(loss/weight(neutral(drugs:!Metformin,!GLPW1!Agonist,!DPPWIV!inhibitors,!Amylin(
• Weight(gain(drugs:!sulfonylureas,!TZDs,!insulin(
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Insulin(is(most(potent!(biggest!reduction!in!HbA1c);!followed(by(Metformin(and(sulfonylureas(
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Other!nonWinsulin!therapies!(not!discussed!in!depth)(
• AlphaWglucosidase!inhibitors!(acarbose,!miglitol)(
• Meglitinides!(repaglinide,!nateglinide)(
• BileWacidWbinding!resin!(colesvelam)(
• DopamineWagonist!(bromocriptine)(
Diabetes(
Disorder(
Type(1(
Diabetes(
Type(2(
Diabetes(
General(Info(&(Causes(
Presentation(
Autoimmune(destruction(of(pancreatic(beta(islet(cells((
Etiology!not!completely!known:!genetics!predisposition!
and/or!environmental!triggers!cause!autoimmunity!that!
decrease!beta!cell!mass!over!time!(clinical!onset!when!have!
lost!80W90%!of!beta!cells)(
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1/300!of!general!population!(1/20!if!have!1st!degree!relative;!
1/1W3!in!monozygotic!twins)(
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Higher!prevalence!in!Western!Europe,!US,!Australia!
(increasing!incidence!by!3W5%!per!year);!low!incidence!in!
China!and!Africa(
Genetics((risk(is(additive)(
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HLA!(accounts!for!50%!of!genetic!risk,!esp!HLAWD!which!codes!
MHC!Class!II)(
• Risk:(HLATDR3/4(
• Protective:!HLAWDQA1*1012,!DQB1*0602!(
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Insulin(gene:!Class!I!VNTR!(tandem!repeats)!within!5’!region!
associated!with!increased!risk!!less!insulin!expressed!in!
thymus=decreased!ability!to!distinguish!insulin!as!self!rather!
than!pathogen(
Environment(

Viruses,!breastfeeding,!timing!of!food!introduction!to!infants,!
hygiene!hypothesis,!accelerator!hypothesis!(obesity!speeds!up!
onset!of!disease);!Vit.!D!may!be!protective(
Associated(coTmorbidities:(Autoimmune!thyroid!(15W20%);(Celiac!
(5W10%);(Addison’s!(1W1.5%)(

Accounts!for!90%!of!diabetes!patients;!5th!leading!cause!of!
death!in!US(
Insulin(resistance(AND(decreased(insulin(secretion(are(
required(to(develop(diabetes((will!be!on!exam!)(
Vicious!cycle!dysfunction!begets!more!dysfunction!unless!
you’re!able!to!intervene(
Insulin(acts(via(PI3K(kinase(to(confer(a(metabolic(signal!
(distinct!from!MAPK!signaling!!growth/mitogenic)!!this(
signal(is(disrupted(in(insulin(resistance(
• Metabolic!signal!disrupted!leads!to!lipolysis!!
release!FFA!!FFA!triggers!hepatic!production!of!
glucose!AND!damage!of!beta!cells!!hyperglycemia(
Also(have(glucagon(dysfunction!b/c!alpha!cells!depend!on!
betaWcell!secretion!to!regulate:!decreased!insulin!!decreased!
inhibition!of!glucagon!secretion!!glucagon!continues!to!
stimulate!liver!to!produce!glucose!!hyperglycemia(
• Incretin(effect!!potentiates!effect!of!insulin!and!
suppresses!glucagon(
About!50%!of!beta!cells!damaged!at!time!of!diagnosis(
Risk(factors:!family!hx,!HTN,!dyslipidemia,!central!obesity,!
gestational!diabetes,!birthweight!>9!lbs!or!SGA,!ethnicity!(AA,!
Hispanic,!Native!American,!Pacific!Islander)(
No(association(with(any(HLA(types(
Associated!coWmorbidities:!Obesity,!hyperlipidemia,!polycytic!
ovary!disease,!fatty!liver!disease(
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

(
(
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Usually(in(childhood((peak!
incidence!is!10W12!yrs!old,!
though!presenting!more!in!<!5!
yrs)!!
Usually!in!normal!weight!
individuals!
Polyuria/nocturia,(polydipsia(
Weight(loss((
Blurry!vision!
Acute!presentation=DKA!
(abdominal!pain,!Kussmaul,!
nausea/vomiting)!
10W20%!have!positive!family!
history!
Labs/Diagnostics(
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Usually!postWpuberty;!usually!
overweight/obese!
Usually!not!associated!with!
ketoacidosis!
Polyuria/nocturia,!polydipsia!
Weight!loss!!
Blurry!vision!
>50%(have(positive(family(
history((
Fasting(glucose(>126(mg/dl!on!2!
occasions!(no!food!for!>8!hrs)!
2!hr!Oral!glucose!tolerance!test!
(OGTT):(>200!mg/dl!
Random(blood(sugar(>200(AND(
symptoms(of(DM(
HbA1c(>(6.5%!on!two!occasions(
Islet(cell(autoantibodies((ICA)(to(
islet(autoantigens((IAT2,(GAD65,(
ZnT8)(or(insulin(itself((mIAA)(
• 2+!ICAs!will!almost!certainly!
progress!to!DM!
• While!there!are!Ab,!most!of!the!
damage!is!TWcell!mediated!(no!
good!test!to!detect!this)!
Decreased!First!Phase!Insulin!
Response!(FPIR=insulin!released!in!1st!
and!3rd!minute!following!IV!glucose)!!
Low(CTpeptide(

!
Diabetes Autoimmunity Study in the Young
(DAISY) found that:

AutoAb are negative until ~8 yrs of age

Clinical signs of DM at 11-15 yrs

If have 2+ positive islet autoAb, they will
get diabetes (just a matter of time)

No(evidence(of(betaTcell(
autoimmunity(

Fasting(glucose(>126!mg/dl!on!2!
occasions!(fasting=no!eating!for!>8!
hrs)!

2!hr!Oral!glucose!tolerance!test!
(OGTT):(>200!mg/dl!

HbA1c(>(6.5%!on!two!occasions!

Random(blood(sugar(>200(AND(
symptoms(of(DM(

First!Phase!Insulin!Response!
(FPIR=insulin!released!in!1st!and!3rd!
minute!following!IV!glucose)!is!usually!
lost!completely;!the!second!phase!is!
normal!or!exaggerated!
!
!
Treatment(

Humanized Insulin (shots
or continuous subcutaneous
insulin infusion)

Statins (only >40 yrs if lipid
profile is normal)

Continuous glucose
monitoring systems
Prevention (no good data yet)

Primary: stopping before
development of autoAb (i.e.
with infant diet changes—
studies ongoing)

Secondary: prevent those
with autoAb from
developing clinical
symptoms (i.e. with oral
insulin—no clear delay in
disease unless had very high
Ab titers)

Tertiary: prevent
progression of disease (i.e.
with anti-CD3 antibodies,
Abatacept)
Many prospective studies are
underway to prevent T1DM; to
date, none have been conclusive.
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
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

Diet and exercise
Statins
Antihypertensives
Oral agents (Metformin
first line; use 2 meds if A1c
is 8-10%)
Usually require insulin
after about 10 years of
disease (or when A1c >
10%, whichever comes
first)
Aggressive management
early on can prevent or
delay complications
Maturity(Onset(
Diabetes(of(the(
Young((MODY)(
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
Gestational(
Diabetes(

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Pancreatic(
Diabetes(



Inherited!form!of!DM;!1W2%!of!DM!in!youth!
Autosomal!Dominant;!mutation(of(glucokinase(gene!and/or!
mitochondrial!genes!!defect!in!“glucose!sensor”!!defect!of!
insulin!secretion!
Insulin(resistance(due(to(hormonal(changes/weight(gain(
Occurs!in!4%!of!pregnant!women(
Risk!factors:!family!hx,!central!obesity,!ethnicity!(AA,!Hispanic,!
Native!American,!Pacific!Islander)(
May!or!may!not!resolve!after!pregnancy!30W40%!will!
develop!T2DM!within!10!years(

DM(resulting(from(removal(of(or(injury(to(pancreas!(i.e.!
surgery,!pancreatitis)!!beta!cell!loss!results!in!insulin!
deficiency!
Lack!glucagon!in!addition!to!insulin!!predisposes!to!
hypoglycemia!
May!occur!in!an!alcoholic!with!liver!disease,!leading!to!
hypoglycemia!(EtOH!impairs!gluconeogenesis)!
Affects!about!21%!of!US!between!40W74!yrs!
Carb!metabolism!is!not!normal!but!not!yet!abnormal!enough!
to!be!classified!as!DM(
Increased!risk!for!macrovascular(disease((MI,(stroke)!and(
progression(to(T2DM!(at!which!point!they!would!also!be!at!
risk!for!microvascular!disease)(
Associated!with!metabolic!syndrome,!which!can!include!
obesity,!dyslipidemia,!and!HTN(
Clustering(of(coTmorbid(conditions(that(contribute(to(
increased(risk(of(macrovascular(disease(

PreTDiabetes'
aka'impaired'
fasting'glucose,'
impaired'
glucose'
tolerance,'
insulin'
resistance'
Metabolic(
Syndrome(


ACUTE((
Complications(
Diabetic(Ketoacidosis((DKA)(

Usually!in!preWdiagnosed!Type!I!DM;!10%!mortality!

Absolute(lack(of(insulin(AND(increased(counterTregulatory(
hormones(

Most(common(precipitant(is(infection,!often!accompanied!
by!misguided!omission!of!insulin!(in!older!pts,!can!be!due!to!
MI,!pneumonmia,!CVA)(

Increased!FFA!from!adipocytes!

Ketogenesis!in!liver!

Intrahepatic!glucagon/catechols!induces!carnitine!
acyltransferase!and!decreased!malonyl!CoA!activity!permitting!
mitochondrial!ketone!production!

Without(insulin,(both(glucose(and(ketones(are(
overproduced(but(underutilized(
Hypoglycemia(and(Hypoglycemia(Unawareness(

Most!common!acute!complication!of!DM;!occurs!more!in!
T1DM!(when!trying!to!control!glucose!with!insulin—
overshoot!and!get!hypoglycemic)(

Glucagon!and!catecholamines!(fast)!and!cortisol!and!growth!
hormone!(slow)!will!increase!glucose!in!hypoglycemic!states(

Hypoglycemia(unawareness:(no(longer(have(adrenergic(
symptoms(of(hypoglycemia(after(many(hypoglycemic(
episodes(
(









Presents!early!in!life!with!
strong!family!history!and!
negative!antibodies!


Usually(presents(in(2nd(or(3rd(
trimester(
Higher!risk!of!delivery!
complications;!tend!to!have!
bigger(babies((macrosomia)!
Child!and!mother!are!both!at!
risk!for!T2DM!later!in!life!!
May!have!malabsorption!
(steatorrhea,!diarrhea,!vitamin!
deficiencies)!
May!be!underweight!
Prone!to!hypoglycemia!



PreWsymptomatic;!highly!
associated!with!metabolic!
syndrome!
Negative(autoantibodies(
See'blood'glucose'level'criteria'above'


Can be treated with
sulfonylureas or insulins
Genetic counseling
Fasting glucose: >95 mg/dl
2-h OGTT: >155 mg/dl
More'details'will'be'given'in'Life'Cycles'
block!

Not discussed

Not'discussed''

Not discussed



Fasting glucose: 100-126 mg/dl
2-h OGTT: 140-200 mg/dl
HbA1c: 5.7-6.4%

Diet and exercise is best
way to prevent diabetes esp
if lose 5-10% of body
weight
Can also add Metformin
Need to do yearly screening
for DM



PreWsymptomatic!(see!criteria)!
Kussmaul(breathing(
Skin(tenting(
Polyuria,!polydipsia,!weight!
loss,!weakness!

Tachycardia,(hypotensive(

N/V,!abdominal!pain!that!
correlates!will!severity!of!
acidosis!

Altered(mental(status!
(drowsy,!stuporous)!

Osmotic!diuresis!leading!to!
severe(dehydration!!leads!to!
decreased!GFR!and!less!
excretion!of!glucose!
Symptoms(are(either(adrenergic!
(too!much!Epi)!or(neuroglycopenic!
(CNS!dysfunction!from!
hypoglycemia)!

Adrenergic:!Sweating,!tremor,!
tachycardia,!anxiety,!hunger!

Neuroglycopenic:!dizzy,!HA,!
confusion,!convulsions,!LOC!
Hypoglycemia(unawareness:(
subdued,(lack(of(adrenergic(sx(



Three or more of the following:

Waist circumference >40 in (men) or
>35 in (women)

Triglycerides >150 mg/dL

HDL <40 (men) or <50 (women)

BP > 130/85

Fasting glucose >100 mg/dL

Diagnosis:(Blood(sugar(>200(and(
evidence(of(ketones((urine/serum)(

ABG!(acidosis);!pH!usually!<7.3!

CounterWreg!hormones!elevated!!

Apparent((not(real)(hyponatremia:!
• To!correct:!Need!to!add!2!mEq!
Na!to!lab!value!for!every!100!
mg/dL!of!excess!serum!glucose!!

K(looks(high(but(is(low(or(nl!
(intracell!K+!exchanged!for!extracell!
H+!!so!K+!looks!highmay!become!
hypokalemic!if!treated!with!fluids)!

HCT!and!Cr!may!be!high!from!
dehydration!

Measure(CTpeptide!to!determine!if!
low!blood!sugar!is!due!to!exogenous!or!
endogenous!insulin!!

Glucose(<70(mg/dl((other'definitions'
have'<50'mg/dl)'
!

Not discussed


IV Fluids
IV Insulin (slow admin to
avoid cerebral edema, esp in
kids)
+/- potassium (depends if
hypokalemic from diuresis)


For hypoglycemia
unawareness: scrupulous
avoidance of hypoglycemia
for 3+ weeks
CHRONIC(
Complications(

MACROVASCULAR(

77%(of(hospitalizations(and(80%(of(mortality(in(DM(is(due(to(CVD(

MI,!stroke,!peripheral!vascular!disease!(2W4x!greater!incidence)!!leading!cause!of!death!in!DM!patients(

Hyperglycemia!causes!endothelial(cell(dysfunction:!decreases!vasoactive!peptides,!secretes!adhesive!molecules,!loses!tight!junctions,!abnl!vascular!
smooth!muscle,!decreased!fibrinolysis!!increased(risk(of(atherosclerosis(and(procoagulation(

T2DM(patients(often(have(HTN!(not!in!T1DM!unless!develop!renal!disease)(

Hyperinsulinemia!(metabolic!syndrome!and!insulin!resistance)!damages!vessel!wall!and!increases!CV!risk(

DM!patients!should!be!treated!as!though!they!have!cardiovascular!disease!(
MICROVASCULAR(
Mechanisms:((

Excess!glucose!stimulates!polyol(pathway!!creates!sorbitol!(via!aldose!reductase),!which!causes!oxidative!damage(

Advanced(glycosylation(end(products((AGEs)!interfere!with!basement!membrane;!impair!vasodilation;!bind!RAGE!receptors!which!causes!
endothelial!dysfunction;!can!crosslink!and!cause!DNA!damage(

AGEs!and!high!sugar!can!increase(PKC!!leads!to!BM!thickening,!increased!ICAMS,!VEGF;!impair!NO!!retinopathy!and!damage(

DM!associated!with!increased!Reactive(Oxygen(Species!(ROS)!!oxidative!damage(
Retinopathy:((

Leading!cause!of!blindness!in!US(

Pericyte!dropWout!!loss!of!autoreg!of!retinal!capillaries!!capillary!drops!out!and!BM!thickens!!leakage!of!intravascular!fluids!leading!to!
hemorrhage!soft!and!hard!exudates!!ischemia!can!lead!to!dilated(vessels!and!angiogenesis(

Stages:!early!preproliferative!!mild!preproliferative!(intervene!with!laser)!!severe!preproliferative!(intervene!with!laser)!!early!proliferative!!
neovascularization!!macular!edema(

Other'complications:'(Macular!edema,!corneal!ulceration,!glaucoma,!cataracts(
Nephropathy(

DM!is!leading!cause!of!renal!failure/dialysis!and!transplant!in!US;!5W10%!of!DM!pts!require!dialysis!(

Hyperfiltration!(high!GFR)!due(to(increased(osmotic(load!!intrarenal(HTN!!BM!thickening!and!mesangial!proliferation!!glomerular!
obliteration(

Screen!for!albumin!(GFR!not!a!good!screen!since!it’s!not!significantly!affected!until!late)!in!urine!(
Neuropathy((due!to!neurotoxic!milieu!of!high!sugar,!polyols,!hypoxia,!oxidant!stress,!etc)!

Mononeuritis(multiplex!(reversible)(

Distal(symmetric(polyneuropathy((most(common;((“stockingT(glove”):(hammerWtoes;!predisposes!to!ulcers,!infection,!and!can!progress!to!
amputation(

Autonomic(neuropathy!(most!fatal):!increased!risk!of!MI;!includes!gastroparesis,!sexual!dysfunction,!orthosatic!hypotension,!hypoglycemia!
unawareness(

Diabetic(amyotrophy!(18W24!months!of!truncal!wasting;!resolves)(
Normal values:
• Fasting glucose <100 mg/dl
• 2-h PG < 140 mg/dl
• HbA1c <5.7

Statins (goal(of(LDL(<100)
decreases mortality and CV
events in DM patients(

Blood pressure control
(goal!BP!is(less(than(
140/90)!decreases CV
mortality in DM pts

Early intensive glycemic
control may decrease
complications
Retinopathy:((

Early(intervention!can!
prevent!70%!of!vision!loss(

Panretinal!
photocoagulation!(first!
line)!+/W!intravitreal!drugs!
(i.e.!antiWVEGF,!
tramcinolone!acetonide)(

Tight!glycemic!control!may!
prevent!or!decrease!vision!
loss(
Nephropathy(

AntiHTN!(ACEIs,!BBs)!+!
glycemic(control!+!
protein!restriction!can!
slow!progression(
Neuropathy

For!distal(symmetric(
polyneuropathy:(Foot!
care,!examination,!
education
Metabolism(Disorders(
Class(
Glycogen(
Storage(
Diseases(
Disorder(
GlucoseT6Tphosphatase(
Deficiency((GSDTI,(Von(
Gierke(Disease)(
General(Info(&(Causes(



Glycogen(
Synthesis(
Disorders(
Glycogen(
Breakdown(
Disorders(
Gluconeogenic(
Disorder(
Hepatic(Glycogen(Synthase(
Deficiency((GSD(0)(

Branching(Enzyme(
Deficiency((GSD(IV,(
Andersen(Disease)(
Phosphorylase(Deficiency(
(GSD(VI)(and(
Phosphorylase(Kinase(
Deficiency((GSD(IX)(
Debranching(Enzyme(
Deficiency((GSDII,(Cori(
Disease)(


Fructose(1T6(
Bisphosphatase(Deficiency(





Most(severe(GSD(
Glucose(can’t(leave(liver!(trapped!as!
G6P)(
Complications!if!poorly!controlled:!
chronic!lactic!acidosis,!hepatic!cancer,!
renal!dysfxn,!osteoporosis(
Inability(to(synthesize(glycogen(
Very!rare!(<0.5%!of!GSDs)(
Accumulation!of!straight!chain!glycogen!
in!liver!and!muscle(
Both!together!account!for!25W30%!of!
GSD;!can’t(break(down(glycogen(
Milder!than!GW6!phosphatase!deficiency(
Accumulation(of(abnormal(glycogen!
in!liver!and!muscle(
Inability(to(generate(glucose(via(
gluconeogenesis(
Can!be!precipitated!by!high!fructose!
ingestion(
Presentation(




















Disorders(of(
Fructose(and(
Galactose(
Hereditary(Fructose(
Intolerance(
Galactosemia(
Disorders(of(
Fat(Oxidation(
Medium(Chain(Acyl(CoA(
Dehydrogenase(Deficiency(
(MCAD)(





Very(Long(Chain(Acyl(CoA(
Dehydrogenase(Deficiency(
(VLCAD)(
CPTT1(Deficiency(
Aldolase(defect!(aldolase!converts!F1P!
to!3WC!compounds!that!enter!glycolysis/!
gluconeogen)!leading!to!F1P(
accumulation,(which(inhibits(
glycolysis(and(gluconeogenesis)(
Galactose=sugar!in!milk(
GALT(enzyme(deficiency((produces!
UDP!galactose)!!can’t!metabolize!
galactose(
Most(common(genetic(cause(of(
impaired(fat(oxidation!!unable!to!
oxidize!medium(chain!fatty!acids(
Increased!glucose!demand!AND!
decreased!glucogneogenesis!(fat!ox!
usually!provides!energy!for!gluconeo)(











Similar!to!MCAD!but!impaired!metab!of!
longer(fatty(acids(



Unable(to(move(fatty(acids(into(
mitochondria(




Treatment(
Usually!present!in!first(year(of(life!with!severe!fasting!
hypoglycemia!occurring!with!3T4(hours(after(a(meal!
Increased!lactate!!acidosis(
Increased!fatty!acid!syn!hyperlipidemia(
Increased!uric!acid!(HMP!shunt)!and!decreased!renal!
excretion!
Fasting!hypoglycemia,!severe!ketotic!hypoglycemia!
Only(GSD(WITHOUT(liver(enlargement(on(exam!
Increased lactate!
Hypoglycemia(not(as(severe((more(weakness(
(myopathy)!and!hepatomegaly!!
Liver!injury!can!be!severe!and!lead!to!death!before!age!6!
Hepatomegaly(
Short!stature!
Mild!muscle!weakness!
Ketotic!hypoglycemia!
Infants!present!with!hepatomegaly!and!hypoglycemia;!
ketones!with!fasting!
Lactate!and!uric!acid!levels!usually!normal!
Delayed!growth/short!stature;!myopathy!
Late(hypoglycemia((after(18T24(hrs!of!fasting)!
NO(hepatomegaly((
Severe!lactic!acidosis!(marked!by!compensatory!
hyperventiliation=resp!alkalosis)!
High!pyruvate!levels!and!ketones!in!fasting!

Inhibition!of!glycolysis!and!gluconeogenesis!leads!to!
hypoglycemia!
Symptoms(with(intro(of(fructose(in(diet((fruits)(and(
worsen(with(high(fructose(ingestion!!N/V,!pallor,!can!
lead!to!coma!
Elevated(LFTs(!may!develop!liver!and!kidney!disease!
BuildWup!of!galactose(injures(liver((jaundice,(
coagulation(problems(
Also!get!galactose!buildWup!in!eyes!!cataracts!
Neuro!sx:!ataxia,!tremor,!speech!impairment!
Failure(to(produce(ketone(bodies(
Presents!in!infancy(to(early(childhood(as(modTtoTsevere(
hypoglycemia(after(12T18(hours(of(fasting,!especially!in!
presence!of!viral!infection(
Increased!levels!of!medium!chain!acyl!carnitines(
Accumulation!of!gluconeo!precursors!in!the!form!of!urinary!
organic!acids(
Similar(to(MCAD(but(may(be(milder/present(later(in(life(
May!have!muscle!soreness!or!rhabdomyolosis!after!exercise!

Dietary fructose restriction

Dietary restriction of galactose

Frequent carb-rich feedings

Frequent carb-rich feedings
Fasting!hypoglycemia!with!low!ketones!
Typically!present!in!infancy!after!vial!illness!
Increased!free!carnitine!but!decreased!acylWcarnitine!
Elevated!ammonia!(from!nitrogen!removed!from!amino!
acids!used!for!gluconeogenesis)!

Frequent carb-rich feedings

Constant supply of glucose to avoid
hypoglycemia
Raw cornstarch allows more widely
spaced feedings of 5-6x/day in older
individuals
Not discussed
Not discussed


Adults can often fast 18-24 hrs
although treatment with raw
cornstarch may improve energy
levels
Seems to improve clinically by
adulthood
Not discussed
Other(Medical(
Causes(of(
Hypoglycemia(








Deficient(CounterTRegulatory(Hormones:(!Includes!glucagon,!cortisol,!epinephrine,!and!growth!hormone!
o
Deficiency!of!cortisol(and(GH(in(hypopituitarism!can!lead!to!hypoglycemia!(will!also!see!midline!defects,!micropenis/undescended!testes,!jaundice,!nystagmus,!etc.)
o
Adrenal!insufficiency!(low!cortisol)!!also!see!poor!growth,!hypotension,!decreased!energy,!etc
Neonates!are!particularly!sensitive!to!low!growth!hormone!and!can!typically!present!with!hypoglycemia!within!<4W12!hrs
Hyperinsulinism: Common hypoglycemia disorders in neonate (can be due to maternal DM or IV glucose to mother during labor/delivery)
o
Perinatal stress (low weight, asphysxia, eclampsia, prematurity) can also induce hyperinsulinemia  treat with diazoxide (Katp channel inhibitor)
o
Also there are 5 protein mutations associated with hyperinsulinism (some responsive to diazoxide, but may need pancreatomy)
Infants of Diabetic Mothers: Neonates are arge for gestational age (macrosmia)  baby secretes high insulin during gestatation in response to mom’s high blood sugar, but once born the baby has
normal glucose but still high insulin secretion  hypoglycemia
o
Characteristic state: Need excessive IV glucose infusion (>8-10mg/kg/min) to be normoglycemic AND absence of ketones; serum insulin concentrations are not suppressed
Ketotic Hypoglycemia: Mcommon cause of hypoglycemia in childhood; usually in 15 month to 5 yrs of age, esp if thin or undernourished  usually grow out of condition
o
Have limited muscle protein  lack of gluconeogenesis substrates decreased gluconeogenesis during illness/decreased food intake
o
Increased blood and urine ketones treat with Ketosticks/juice/glucose-containing foods
Insulinoma: Tumors of endocrine pancreas that makes insulin  in adults, may be associated with MEN-1
o
High C-peptide, low blood sugar, low ketones (diagnose after 72 hr fast and check C-peptide and BG levels)
Insulin Overdose: Mismanagement of diabetes or mistakenly given  should have low C-peptide
Sulfonylurea Ingestion: Overdose or inadvertent ingestion of sulfonylureas  will have high insulin, high C-peptide, and positive sulfonylurea screen
Ethanol Ingestion: Ethanol leads to high levels of NADH, which inhibits gluconeogenesis and drives production of lactate  hypoglycemia usually occurs in alcoholic who is ingesting large
quantities of alcohol without eating carbs
Other: salicylate intoxication, diarrhea/malnutrition, Dumping syndrome, disorders of amino acid metabolism, etc

Notes

Hypoglycemia will be defined as glucose <50 mg/dL with resolution upon glucose ingestion
• Clinical signs include: Adrenergic (sweating, shaky, tachycardia, weakeness, hunger) and neuroglycopenic symptoms (irritability, tremor, seizures, decreased consciousness, or coma
• Labs (should obtain urine and blood samples at time of hypoglycemia, BEFORE treatment)

Plasma venous sample glucose <50 mg/dl  also want to measure insulin, bicarb, cortisol, GH, Ketones, free fatty acids, lactate and pyruvate (suspected GSD), C-peptide, carnitine

Urine sample: measure ketones and organic acids, urine-reducing substances (“non-gluose) in newborns with suspected galactosemia

In neonates (controversial)  present more with fussiness, lethary, tremor, trouble feeding
•
Within first 12 hrs: <30 mg/dl
•
After 12 hrs: <45
•
After 2 d: < 50
•
Premies and SGA infants have higher rates of BG< 30 after 3-6 hrs of fasting

Can be precipitated by fasting, illness, exercise, ingestion of certain sugar (i.e. galactose or fructose)

Presence of ketones separates defects in fat oxidation (no ketones) from glucose metabolism (plus ketones)
• Brain, renal cortex and RBCs are obligate glucose utilizers (can’t use ketones in the short term)  deficient ketone production makes ALL tissues obligate glucose utilizers = hypoglycemia

Hypoglycemia and Timing
• < 4 – 6 hours after eating:

Glucose 6 phosphatase deficiency

Milder GSDs 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

Fatty acid oxidation disorders in older children and adult
Dyslipidemias(
Disorder(
High(LDL(
High(Triglycerides(
Increased(NonTHDL((
(VLDL,(IDL,(LDL)(
General(Info(&(Causes(
Calculating(LDL(

The(level(of(LDL(cholesterol(is(closely(related(to(CVD(risk(and(is(amenable(to(treatment.((Thus(LDL(is(the(most(important(lipid(parameter(to(address(clinically.(((

Difficult!to!measure!LDL!directly!so!use!Freidewald!Formula:!LDL=(Total(Cholesterol(–(HDL(–((Triglycerides(÷(5)(

VLDL(=Triglycerides(÷(5!!!ONLY(if(triglycerides(<400mg/L((i.e.!when!no!chylomicrons!present!in!blood)!

Total(cholesterol(should(be(<200(mg!

Chylomicrons'and'IDL'rarely'present'in'blood'which'is'why'it’s'not'in'formula(
!
Determining(LDL(Goal(Based(on(CVD(Risk(Stratification(

>20!yrs!old!lipid!panel!every!five!years!
Risk(Factors:(
Number of Risk Factors
Goal LDL-C

Age!(male!≥45!years,!Female!≥55!years)!
0-1
160 mg/dl

Family(history!of!premature!coronary!heart!disease!(CHD)!
≥2
130 mg/dl

CHD!in!male(first(degree(relative!<55!years!
100 mg/dl is a therapeutic option
10 year risk <20%

CHD!in!female(first(degree(relative!<65!yrs!
CHD and CHD risk equivalents
100 mg/dl

Current!cigarette!smoking!
(other forms of atherosclerotic disease,
70 mg/dl is a “therapeutic

Hypertension!(Blood(pressure(>140/90!or!on!antihypertensive!medications)!
Diabetes, or a 10-year risk >20%)
option” that is favored by many

Low!HDL!(HDL<40!mg/dl)!
physicians now

Elevated'HDL'(HDL'≥'60'mg/dl)'counts'as'a'‘negative’'risk'factor'
The'absolute'risk'of'a'CHD'event'is'estimated'from'Framingham'Risk'Score'
Determining(the(Cause(of(High(LDL(

Assessment!includes!blood!glucose,!HbA1C,!TSH,!LFTs,!creatinine,!urine!protein(

Increased(LDL(Production:!(
• Overproduction!of!VLDL!by!liver!(i.e.!in!insulin!resistance);!usually!also!see!increases!in!apo!B(

Decreased(LDL(Catabolism:((
• Familial(Hyperchoesterolemia(

1/500;!autosomal!dominant(

Half!don’t!have!LDLWreceptor;!other!half!have!defective(LDL(receptors(

Elevated!LDL!leading!to!premature!death!(before!20!yrs!in!homozygotes)(

Presentation:!arcus(cornealis,(xanthelasma(and/or(tendinous(xanthomata(

Aside:'PCSK9'mutations'lead'to'less'degradation'of'LDL'receptor''decreased'LDL'and'less'CVD'events;'gain'of'function'PCSK9'mutations'can'resemble'FH'
• Decreased(LDL(clearance:!diets!high!in!saturated!or!trans!fats:!hypothyroidism;!nephrotic!syndrome,!cyclosporin(

Normal(fasting(TGs(<150(mg/dL(

If!serum!gets!very!high!>1000!mg/dl,!serum!can!look!lipemic!(milky)!and!can!lead!to!pancreatitis(

Determining!cause:!Rule!out!secondary!causes!by!measuring!TSH,!creatinine,!LFTs,!fasting!glucose,!urine!protein,!H!&!P,!medications(
• Increased(VLDL(Production(

Most!commonly!from!insulin(resistance!insulin!does!not!have!appropriate!antiWlipolytic!effect(
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Drugs:!protease!inhibitors!(HIV!drugs)!and!oral!estrogens!(kidney!disease!can!further!contribute)(
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Alcohol:!promotes!formation!of!fatty!acids!via!lipogenesis!from!ethanol!carbons(
• Decreased(TGTrich(Lipoprotein(Catabolism(
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Primary(defects:!LPL!or!C2!deficiency;!familial!dysbetalipoproteinemia!(see!below)(
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Secondary!to!DM,!alcohol,!renal!failure(
• Severe(Hypertriglyceridemia:!if!TGs>1000(mg/dl,!it’s!usually!because!chylomicrons!are!also!circulating;!can!occur!with!defects!along!any!step!of!the!pathway(
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Symptoms!of!severe!hypertriglyceridemia!(usually!genetic!cause):!lipemia(retinalis,(eruptive(xanthomas,(hepatosplenomegaly(
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Remnant!Hypothesis!(buildup!of!remnants!from!VLDL/chylomicron!metabolism)!vs!Lipolytic!toxin!hypothesis!(FAs!themselves!are!toxic)!for!proposed!CAD!mechanism!(
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In!women,!if!control!for!HDL,!the!TGs!themselves!are!correlated!with!disease(
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NonTHDL((all!apoBW100!containing!lipoproteins=VLDL,!IDL,!LDL)(=(Total(cholesterolTHDL!
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May!be!better!predictor!of!CVD!events!than!LDL!alone!
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Familial(Dysbetalipoproteinemia(
• Autosomal!Recessive;!defect!in!IDL!and!remnant!catabolism!from!having!an!Apo(E2(allele!(rather!than!E3!or!E4)!(
• Leads!to!decreased!clearance!and!ILD/remnant!accumulation!(Apo!E2!doesn’t!bind!hepatic!receptors!correctly)(
• Diagnose(with(lipoprotein(electrophoresis,(Apo(E(genotype!(Aside:'talk'with'patient'since'may'discover'pt'has'E4'allele,'correlated'with'Alzheimer’s)'
• Symptoms:!planar!xanthomata!(palms/soles);!premature!atherosclerosis(
(
Low(HDL(
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Increased(Lipoprotein(
(a)(
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Low(HDL(is(<40(mg/dl((women)(and(<(50(mg/dl((men)!associated!with!increased!risk!for!CVD!(high!levels!of!HDL!are!protective)!!BUT!no!evidence!that!raising!HDL!with(
drugs!is!significantly!beneficial!(but!drinking!wine!does!increase!HDL)!
Genetic(Causes:!
• Mutations!in!ABCTA1:!Tangier(Disease!(Auto!Dom;!“orange!tonsils”)!and!Familial(HDL(Deficiency!(Auto!Dom)!!both!associated!with!premature!atherosclerosis!
• Mutations!in!LCAT:!LCAT(Deficiency!leading!to!corneal!opacities!(“fish!eye”!syndrome)!but!not!necessarily!associated!with!increased!CVD!risk!
• Mutations!in!ApoTA1:!Familial(Hypoalphalipoproteinemia!(auto!dom)!linked!with!premature!atherosclerosis!
Acquired:!high!carb!diet,!obesity,!drugs!(BBs,!diuretics,!progestings,!androgens,!protease!inhibitors),!smoking!!
Apo!(a)!apolipoprotein!linked!by!single!disulfide!bridge!to!LDL!apo!B!=!Lipoprotein!(a)!
Function!unknown!but!associated!with!premature!atheroslerosis!(esp!in!women)!
Resembles(plasminogen((promotes(clotting)(
NOTES(
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Fat!droplets!(high!TGs)!in!muscle!!seen!in!elite!athletes!and!in!insulin!resistance!
Treatment!!
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Reducing!LDL:!Statins!and!other!therapies!
• Statin(Benefit(Groups(
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Clinical!CVD!
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LDL(>190(mg/dl(
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Primary!prevention:!DM,!ages!40W75!yrs,!LDL!70W189!mg/dl!
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Primary!prevention:!No!DM,!age!40W75!yrs,!LDL!70W189!+!7.5%!risk!of!CVD!event!in!next!10!years!
• Statins:!Inhibit!HMG!CoA,!which!reduces(production(of(LDL(AND(increases(LDL(receptor(expression!(increases!LDL!clearance)!
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Risuvastatin!most!potent>!atorvastatin>!simvastatin!
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Know(the(6%(rule:!For!each!dose!doubling,!LDL!only!fall!by!6%!(use!to!weigh!benefits!vs!side!effects)!
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Side!Effects:!Dose!related!changes!in!AST!and!ALT!(hepatic!injury);!myopathies!(myalgias,!myosities,!rhabdomyolysis;!major!determinant!is!SLCO1b1*5!allele),!new!onset!T2DM!(1.1%!
increase!in!risk),!cognitive!impairment!(rare)!
• Other!cholesterolWreducing!therapies!
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Sterol!transporter!inhibitors!(Ezetimibe)!!second!line!
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Plant!sterols!(not!good!evidence!for!decreasing!CVD)!
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Inhibit!Bile!Acid!resorption!of!cholesterol!
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TriglycerideTReducing(Drugs!(Statins,!Fibrates,!OmegaW3!oils,!niacin)!
!
CVD risk
Mechanism of ↑ risk
Clinical trials showing risk reduction
High LDL-C
Consistently ↑
Biochemical modification
Multiple RCTs
& resultant inflammation
High triglycerides
Variably ↑
Not clear why risk is ↑
Minimal data
Low HDL-C
Variably ↑
Reduced reverse cholesterol
Minimal data
transport?
!