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90 Cards in this Set

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What are the types of symmetric neuropathies of DM?
1) Distal, primary sensory polyneuropathy (can be either mainly marge fibers, small fibers or mixed)
2) Autonomic neuropathy
3) chronic evolving proximal motor neuropathy


often caused by osmotic pressure on then nerves from the hyperglycemia / sorbitol / polyol damage

ex1: foot with cocked toes due to loss of motor fc in the extensors > flexors --> ulcer under foot due to no sensation = most common from is this mixed kind;

ex2: autonomic destruction leads to the sudden death in DM because the warning signs of an MI are missing - also no sensation of the angina...
What are the types of asymmetric neuropathies of DM?
1) Acute or subacute proximal motor neuropathy
2) cranial mononeuropathy
3) Truncal neuropathy
4) Entrapment neuropathy in the limbs

mechanism is mostly ischemic damage due to blockage of vasa vasorum, so there is often PAIN first and then dysfct:

ex1: wrist drop after falling asleep on arm: radial nerve damage = mononeuritis simplex

ex2: CN3 palsy causing double vision and unability to look up; but the pupils REACT, because that's regulated by parasympathetic - which runs on the inside of then nerve closest to the blood vessel - is it's affected last = mononeuritis simplex

ex3: atrophy of all the hamstring muscles = Amyotrophy - diabetic myopathy - misnomer bc it's the nerve, not the muscle; this is Mononeuritis multiplex
Sulfonylurea
long acting Secretagogue
for basal glucose control

blocking the K+ channel causes depolarization --> Ca channel opening --> inceased Ca in cell causes release of Insulin

SE: problem is: Hypoglycemia (you have to eat because you're constantly emitting insulin)

SE: weight gain, SIADH

depends on the presence of b-cells
Repaglinide, Nateglinide
short acting secretagoges
for post-prandial control of glucose

blocking the K+ channel causes depolarization --> Ca channel opening --> inceased Ca in cell causes release of Insulin

SE: problem is: Hypoglycemia (you have to eat because you're constantly emitting insulin)

SE: weight gain, SIADH
Biguanide
Metformin

activation of AMP-Kinase --> signals that we have apparently "low energy" so we get increased fatty acid oxidation and hepatic glucose production as well as decreased glycolysis and more muscle uptake.


SE: problem is: Patients with heart conditions or chronic liver disease, or lung disease --> increased risk of lactic acidosis

SE: Lactic acidosis, weight loss, Diarrhea
Thiazolidinediones
TZD's = insulin sensitizers

Rosiglitazone, Pioglitazone

nuclear receptor PPAR-y activation -- more gene activation for insulin production

act primarily on adipose cells and secondarily sensitize muscle cells to insulin. (Lipodystrophy study moved fat from the wrong places = inside the organs, to the right places)

Side effect: Heart failure!, weight gain
a-glucosidase inhibitors
Acarbose, Mitigol
inhibit the absorption of carbohydrates by inhibiting the breakdown to glucose --> malabsorption

for post-prandial hyperglycemia

SE: some weight loss, but flatulence
intensive DM therapy
must be multifactorial - treating all risk factors such as high LDL, HTN, body fat (provides 50% increased risk reduction)

The A1c control eventually reaches the same lvl as the conventional and the slope of increase is the same too - due to loss of beta cells

BUT at least we can prevent to microvascular complications (not necessarily what they die from)

BUT even after 10yrs later, we still have benefit from the tight glucose control: still have less mortality from CV
Diabetes diet
calories from
30% fat - better saturated
50% carbs - better complex ones
15% protein
low salt

type II DM is same, just also includes calorie reduction overall
before we do pharmacotherapy with DM, what do we order
Exercise and Weight loss
GLP-1 analog
GLP-1 analog: the spit from the dragon gives us Exanatide® which is an incretin. These are substances secreted in the anticipation of getting a meal – act on pancreas to secrete insulin

DM have blunting of GLP-1
Amylin
Pramlintide (tradename)

synergizes with insulin
types of insulin
Lispro/Aspart = fast acting (fish insulin - only 2 aa different from human, but faster action)

NPH = neutral protamine hagedorn = intermediate acting

Lente and Ultralente = long acting

Glargine = ultra-long acting; peak-LESS insulin, prevents DKA
autonomic neuropathy in DM examples
Cardiovascular: orthostatic hypotension, tachycardia, sudden death

Gastroparesis (devestating, can't dose insulin well)

Erectile dysfunction

Cystopathy (large post-void residual - ifections)

Sudomotor disorders

Hypoglycemia unawareness (sweats and others are missing)
erectile dysfunction in DM
not purely neuropathic, it's a marker for CV disease
Sildenafil
PDE-5 inhibitor --> constant cGMP increase --> dialate blood vessels in penis

least effective in DM because they don't have a pure neuropathy or a pure vasculopathy

(if it were pure n or v, sildenafil might be able to overcome the it)

but still 1/3 are helped
valsalva with DM?
deep breath, strain
breath normal

test finds the changes in the puls and respiration --> changes in sympathetic and parasympathetic

normally you should get sinus arrhyhmia with HR changes

DM loose this: they'll have a relatively constant pulse

do this bc: autonomic NS loss causes sudden cardiac death in DM!
skin findings in DM
1) 50-60% will get diabetic dermopathy
past - bad control of DM

2) Necrobiosis lipodica diabeticor - infarction of the fat under the skin
strategies to reduce microvascular complications

why?
how?
prevention is proven to work by intervetion on:
hyperglycemia
hypertension

treatments proven by intervention trials:
-ACE inhibitiors for neuropathy
-Laser photocoagulation for retinopathy
what are the macrovascular complications of DM
Angina, exercise intolerance (if ANS neuropathy - silent) ---> CAD (2-3x higher; 4x higher risk of dying during MI; 2x higher risk of dying post-MI, also higher risks in Impaired Fasting Glucose pt)

Claudication ---> PVD

TIA's, strokes --> CVA

Renal artery sclerosis ---> renal failure
Risk of MI in people with DM and without
risk of MI in DM if you've never had an MI = same as risk of non-DM who's had an MI

same in several ethnic populations
what causes the increased CVD in DM?
hyperclycemia: as it increases, the risk increases

even before HA1c is before 6 it increaes the risk - so even though in the nl population without DM
pattern of DM dyslipidemia
increased fraction of small, dense LDL-cholesterol (without increase in total quantitiy of LDL-C) - more atherogenic

high TG (independent strong risk factor proven only for DM)

low HDL

Postprandial lipemia (free FA are high in DM persistently)
pathophys of macro-vasc dz in DM
"AGE" of endothelial proteins

HTN

accelerated artheroscleros

Dyslipidemia (peculiar type)
prevention of macrovascular complications
Consider:

HTN
Hyperglycemia
Obesity
Cigarrette smoking
Dyslipidemia
Altered coagulation, platelet fct, fibrinosis,
Nephropathy
Insulin resistance
early and aggressive tx to reduce macrovascular complications
dyslipidemia
HTN
anti-platelet

(not proven yet - thrombolysis, endothelial disorders)
skin finding from severe dyslipidemia
Eruptive Xanthomas - look like red bumps = blobs of VLDL
normally, how do we break TG

changes with insulin type I?
hormone sensitive lipase(HSL) turns the TG into FFA and ships it to the liver --> makes more ApoB, VLDL, TG --> VLDL is released and transported to fat cells and LPL turns it into fat; (LPL prevents the conversion of VLDL into IDL -- LDL)


Changes in DM I:

1) Insulin stops HSL and activates LPL
--> greater influx of FFA to liver
---> more VLDL
also the VLDL is not taken up by the fat cells
--------> shunting to IDL and LDL

2) CETP = cholesterol transporter protein is increased in DM:
a)it moves cholesterol from LDL into VLDL and it and moves TG from VLDL into LDL --> we get a small LDL
b) moves cholesterol from HDL to VLDL, and TG from VLDL to HDL

---> depletes VLDL of TG and depletes HDL/LDL of cholesterol

THIS is the reason for "low HDL" "nl LDL" because they measure the cholersterol in there - however these modified lipid particles are more artherogenic
management of Dyslipidemia
ATP III diet for metabolic syndrome

Hyper-TG / low HDL-C: Niacin (blocks release of FA), Fibrates(activates the oxidization of FA)

LDL-C: statins

Combinations (beware of rhabdomyolysis -- renal disease)
what type of obesity is worse?

fat location
apple shaped - MALE pattern of putting on fat is worse
= the central fat is more toxic
(means more visceral obesity ---> higher TG, higher cholesterol, lower HDL, more insulin resistance)


pear shaped - women is better
management of AMI in DM
b-blockers
ASA
ACE inhib

Angiopasty vs bypass ?? angioplasty might be worse for DM

Glucose control even in hospital:
-continuous intravenous insulin
-followed by intensive glucose control
"HONK"
HHNS

extreme hyperglycemia
-poorly treated/undetected DM
-renal insufficiency
-age/mental obtundation -> decreased oral fluids

absence of ketosis
-insulin is not totally deficient

severe dehydration and volume depletion

coexisting chronic illnesses

high mortality
what should you calculate with HONK presentation
effective osmolariy


2(Na) + glucose/18 + BUN/2.8

if it's over 300 --> person is hyperosmolar (must be there if you want to diagnose HONK)

important bc > 330 greatly increases the risk for seizures and increased mental obtundation
HHNS treatment
Isotonic and hypotonic fluids (unlike DKA, where the main problem is isotonic loss with some degree of free water loss, in HONK it's a mix of both - with tremendous hypovolemia + tremendous dehydration)
(first enough volume, till pressure is restored - and then start giving water to correct the Na)
MONITOR
electrolyte replacement
Insulin (no longer on top)
Treatment
difference btw dehydration and hypovolemia
loss of salt and water in nl proportion = hypovolemia; no good blood tests - Na is variable;
(BP, skin turgur, urine output)

loss of water alone = dehydration; plasma Na is high
Lactic acidosis

why is DM more prone?
causes?
type?
normal healthy persion will have LA <1
well controlled DM has higher baseline >1
DM more prone, also bc tendency of vascular disease and also bc drugs for DM can cause this


CAUSES (2)
Lack of Oxygen or a Toxin that prevents the pyruvate dehydrogenase shunt to the krebs cycle:

Types (2)

with hypoxemia/shock(type A)
without hypoxemia/shock (typeB)
-illnesses
-toxins
-hereditary
-miscellaneous
what contributes to lactic acidosis in DM?
Hypotension (acute GI hemorrhage, sepsis, pancreatits)

Arterial oxygen desaturation

Decreased Cardiac output

Regional hypoperfusion

Drugs (Metformin)
biochemical basis of lactic acidosis
Glycolysis supplies ATP but requires NAD

Pyruvate to Lactate sustains the cycle because it yields fresh NAD

self-sustaining
treatment of lactic acidosis
1) correct hypoxia

2) remove toxins

bicarbonate (caution because more CO2 --> pH more acidic if you can't blow it off)

dichloroacetate (for one condition in children - shunts more oxygen down )
serious complications of DM
retinopathy
nephropathy (leading cause of ESRD)
neuropathy (feet hurt like hell, ED, paresthesias..)
stroke
CVD
Retinopathy

causes
can be traced to a glucose alone phenomenon - more than the others

increased polyol accumulation --> deminishes myo-inositol

formation of AGE's - becomes a problem if glucose sticks to a protein that makes up the BM of a vessel -- makes blidness

increased oxygen stress

increased protein kinase C - beta activity = leakage of vessel
Polypol pathway
D-glucose -- sorbitol -- fructose

more sorbitol = it's more poorely metabolized and so it sits there and causes osmosis --> swelling
AGE's

where from?
Shiff base...
Shiff base still reversible, but then Amadori product --- further products

if Hg is glycosylated it's that way for ever- till the RBC dies - A1c is that
- so it's used to measure
eye disease in DM

frequency
stages
3causes of blindness in DM
1/2 of all DM
incidence is not parallel to nephropathy - it flattens out after 25y

Stages
-Background - microaneurisms, dot-blot hemorhage, hard exudates(white)

-pre-prolif: soft exudates, IRMA, large hemorrhage

-Proliferative - hypoxia causes Neovascularization (= key for prevention of blindness)
[increased endothelial cells and less pericytes cause leaky vessels and hypoxia --> VEGF/PKC --> angiogenesis , vitreal and retinal]

circinate exudates = warning of impending macular edema [ other cause of blindness besides neovascularization and bleeding ] - before they get angio

pre-retinal hemorrhage - serous complication of proliferative retinop

chronic complications of neovasc after bleed-- vitreus pulls on retina -
laser ablation of which vessels?
photo-coagulation
pan-retinal laser destroys the vessels on the periphery and leaves the center of the macula; central area is clean

this is supposed to shunt the blood to the right areas, preventing blindnes
Rubeosis iridis
neovascularization of the IRIS
glycemic control and retinopathy

DCCT
trial convinced us that
intensive glucose Rx reduced development of

retinopathy

- the microvascular complications at least
with the glucose control + eye doctor
kidney disease in DM
very high morbidity and mortality type 1 > type 2

distinct susceptibility genes
-Na/H pump overexpression
-ethnic differences
-simpling pair analysis
natural Hx of kidney disease

MEMORIZE THIS
larger kidney - GFR higher
(increased pressure is actually bad)
creatinine is great in the silent period
but if you dont' do anything, the'll get proteinuria, azotemia and then ESRD


3yrs prior to onset of DM:
-GFR 120, creat 1, ureaN 15

onset of DM
-GFR 150, creat 0.8, ureaN 10

3yrs post onset: Diabetic Glomerulosclerosis
-GFR 150, creat 0.8, ureaN 10

MICROALBUMINURIA
(earliest sign - seen in the silent period - test: must be able to find low lvl of albumin - here we can still slow it down)

-15yrs post onset of DN: time of silent period is over: onset of proteinuria
-GFR 120, creat 1, ureaN 15


20yrs post onsetDM: Azotemia
-GFR 60, creat >2, ureaN >30


23yrs post onset DM: ESRD
-GFR <10, creat >10, ureaN >110
renal changes in DM
1) renal hyperfiltration
2) renal lesions without clinical signs
(microalbuminuria)
3) Nephropathy (microalbuminuria)
Kippel-wilson
4) ESRD


Focal glomerulosclerosis
hemodialysis
only prolongs life by another 5-6yrs
Albuminuria
normal <20
Microaluminuria 30mg - 300 / 24h
Macroalbuminuria >300
- increased risk for renal disease and macrovascular disease

so microalbumin is almost as impotant as a signal as high LDL for risk of MI
why ACE - I?

cant give to?
in addition to glycemic control, for nephrotic prevention:

ACE-I because the pressure must be dropped by releasing the efferent constriction

BUT we can't give it to sb who already has afferent disease because they won't have enough flow to the kidney at all
proximal/afferent vascular disease?
put them on a small dose of the ACE-I

if the creatinine goes up - you know you can't use up because they already have afferent arterioal disese
most common chronic complication of DM

pathology?
nervous system dysfunction
ex: ED

sensory, motor, cranial, autonomic


Types:
Symmetric is most common
Asymmetric
Radiculopathy
Autonomic




Pathology:
distal, multiple neuropathies -- usually polyol pathway

proximal, mononeuropathies usually vascular
Parent or Sibling with DM what's worse?

for DM type I ?
and for DM type 2?
For DM I it's higher risk if sibling had it

For DM II it's higher if parents had it (45% if they both had onset <50; identical twin 60%)
MODY

type of defect?
maturity onset diabetes of youth

type II DM

the genes associated with each of the MODY syndromes is mostly to do with the insulin secretion rather than insulin action; so they're b-cell defects

startling, because the whole time we thought that DM type II was a problem of insulin action - not a destruction of the b-cells ( = type I);

but apparently the MODY's are type II because they don't need that much insulin
Calpain-10, TCF7-L2
genes that are part of the group that cause the common DM type II
polygenetic - common forms of DMII

are still functions of the b-cell!!
Glucokinase

mutation?
Glucose is converted to Glucose-6P
this is the beginning of the glucose breakdown to ATP which eventually tells the cells that they need to make insulin; it's sometimes called the insulin sensor because of that

MODY-2 has a mutation in this
they have a higher "set point" because they're not effectively sensing the glucose --> they'll have a mild stable hyperglycemia
- they have an altered setpoint
2 principles of type 2 DM

2 starting points --- >>>
Insulin resistance + b-cell dysfunction
(+ environment)
I I
I I
Inpaired Glucose TOlerance
I
Type II DM

from this further Gluco-/Lipo- Toxicity leads to more insulin resistance and more b-cell dysfunction


often not detected till it's type 2 and it's already in the vicious cycle
stages of type II DM

path to the development of DM
Peripheral insulin resistance (high insulin) / b-cell dysfunction ---> Impaired glucose tolerance ---> early b-cell damage --> early DM --> late bcell damage --> late DM
5 acute complications of DM
Insulin-induced hypoglycemia
DKA
Hyperosmolar hyperglycemic nonketotic state (HONK)
Lactic acidosis
Hypoglycemic reactions

2 types
Neurogenic: (Sympathetic and parasympathetic activation)
-sweating
-hungry
-tingling
-shaky
-heart pounding
-nervous/anxious

neuroglycopenic (CNS symptoms):
-warm
-weak
-difficulty in thinking
-tired / drowsy
-faint
-dizzy
-difficulty speaking
-blurred vision


these are to be considered separately because they have different thresholds - usually you get the autonomic sx first; however, DM pt with neurpathic damage might loose the neurogenic signs and the first presentation is the seizure
insulin injection
release of Epi (very high) and Ne fast

little bit later glucagon
cortisol
GH
DKAhave to have all 3:
hyperglycemia: osmotic diuresis, volume depletion, dehydration

ketoacidosis: anion-gap acidosis

other metablic changes
how do we get DKA

K:
the ketones
adipocyte release FFA
the controls is via insulin/glucagon ratio

Liver turns the FFA into Ketone bodies or TG; The production into Ketone is also under control of: insulin/glucagon ratio

high insulin and low glucagon prevent the DKA - so the DM pt has a perfect set up:
decreased insulin --> lipolysis --> FFA to liver

+

increased glucagon --> increased hepatic carnitine content/decreased malonyl CoA : so now the FFA can get into the mitochondria--> activation of CAT

--> accelerated ketones

both together cause the ketones
reason for tipping to DKA
historical: they're type I and something that tipped it over:

-alcohol, drugs, infection , MI/stroke, trauma, pregnancy, didn't take their insulin

but now we know:
Blacks and Hispanics have almost equal chance of being type I or type II phenotype when they are found w/ DKA; so now we consider:

"Ketosis - prone - DM" KPD
DKA: D: hyperglycemia

cause:

effects:
hyperglycemia
cause: insulin deficiency, leading to increased hepatic glucose production
decreased peripheral glucose utilization


effect:
-osmotic effect: water pulled from ICF to ECF, osmotic diuresis
-ECF volume:
-Renal loss of water > electrolytes
volume depletion
some degree of dehydration
DKA: A: metabolic acidosis
cause:

effects:
cause:
-xs acetoacetic acid and b-OH butyric acid production
-deminished renal excretion of H+

effect:
-H+ HCO- ---- H2CO3 -- CO2 H2O
ultimate correction of H+ xs depends on:
oxidation of AAA + bOHB, renal excretion of H+
-exchange of H+ for Na
-anemia --> ammonium
loss of electrolytes in urine
water and electrolyte imbalance in DKA
cause:
-osmotic diuresis
-vomiting
-increased aldo
-ICF - ECF shift (K+ PO4)

effect:
-10% body weight loss as fluid!!
50% extracell, 50% intra
-loss of:
K+, Na+, PO4-
symptons of DKA
N/V
polyuria/polydipsia
abdominal pains
mental changes (leathery to near-coma)

signs:
-fruity breath (due to acetone)
-Kussmaul respirations (rapid, deep breaths pH7.2 or less)
-signs of volume depletion (tachycardia, orthostatic hypoTN)
-sings related to precipitating factors (infection , MI, trauma)
Labs of DKA
elevated blood glucose
pH < 7.35
low HCO3-
high anion gap
positive serum ketones
calculation of corrected Na concentration
you expect them to be hypernatremic bc. so much water loss, but the pt is often "hyponatremic" when you see them : artificially bc glucose is sucking water in the blood;

tells you what the pt would have been without the glucose

Na + 1.6 (glucose - 100) / 100
Anion Gap
Na - (Cl + HCO3) = 8-12 (+/-2 )

if it's 14, it's already enough

check if it's complex or simple
DKA treatment

order
Isotonic fluids
Insulin
potassium
Monitor
treat precipitating cause
who get's HONK
older folks who don't have
typical type I DM

not a complete lack of insulin

it's like DKA without ketones

the glucose will be like 900!!!
they have other things that prevent them from drinking...
Besides type I or II what other conditions could you classify the diabetic as?
Cushings disease - pituitary adenoma
Obesity
Addisons (autoimmune disorder, as is DM I, also check thyroiditis pt for this)

Drug or chemical induced

Turners
Klinefelters

X-linked insulin receptor mutation

Gestational DM
Gestational DM
induces insulin resistance

2-13% of pregnant women get DM (higher in AA < asian ) , usually 2nd - 3rd trimester

GDM is associated with increased fetal and materal morbidity

xs morbidity can be reased by maintaining normoglycemia:

increase in insulin production to compensate for the insulin resistance; you can also give her insulin

diagnostic criteria by OGTT; very strict - lower than non-preg;

after delivery, risk of type II is 30-40% in 10yrs
risk of getting type I DM

a) no Fhx
b) father with type I
c) mother with type I; <25yo @ child birth
d) mother with type I > 25yo
e) sibling
a) 1%

b) 6%
c) 4%
d) 1%

sibling 5-10%

2 relatives 20%
identical twin 25-50%
autoimmune type I DM

genes
HLA DQA1, B1, B1 ((chromosome 6)

cytokines

T-cell

b-cell: insulin
environmental triggers of autoimmune DM
coxackie,
milk
markers for type I DM
GAD antibodies - glutamic acid decraboxylase antibodies

antibodies against IA-2 (b-cell phosphatase)

antibodies against ZnT8

antibodies against Insulin


serum from the pt looking for Igs fluorescence

the titers rise years before the onset of DM (is this the incubation period?)
progression of DM type I
genetic predisposition

immunologic abnomalities

progressive impairment in insulin release

presentation at doctor


80% loss of b-cells

give insulin --> honeymoon period

but then overt DM
Risks for type II DM
Native american > mexican > african americans > caucasians

obesity

metabolic syndrome (IGT/IFG)[low HDL, high LDL, HTN, waist cicrumference]

environment (sedentary, fast food)
factors progressing IGT to type 2 DM
insulin resistance / hyperinsulenmia
central obesity
hyerTG
HDL <35
HTN
family x
Hx of gestational DM
inputs into/causing: Insulin resistance


outputs?
Aging, medications (steroids, b-blockers), Fat cell defects, obesity and inactivity, genetic abnormalities, type 2 DM

----> hypertension, Dyslipidemia, Atherosclerosis, PCOS

as long as the b-cell is ok, this will still not give you DM - but if it starts dying...
changes in insulin secretion, glucose disposal and blood glucose
normal person has high normal insulin with high glucose excretion

obese pt has higher insulin and lower glucose excretion

IGT pt has peak insulin and lowest glucose excretion

"here the pancreas is still trying to compensate for the insulin resistance by making more insulin, but then it gives up: ..."

early diabetic has low insulin and still lowest glucose excretion

late DM - insulin down and so is gluc excretion

pancreas is failed

at the very end, the type II DM becomes a type I DM
DM skin
acanthosis nigircans
diagnostic criteria for diabetes
symptoms + random plasma glucose >200

or

FG >125 (= 126 or higher)

or

OGTT > 200
diagnostic criteria for impaired glucose tolerance
FG: >100 - 125

OGTT 140 - 200