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Diabetes Mellitus: Pathology

Name the rash that SSL is going to ask about on the final exam.
necrobiosis lipoidica diabeticorum

Where does diabetes rank in the leading causes of death in the US?
7th

Approximately how many people in the US are affected?
16 million
half undiagnosed

Define diabetes.
A group of metabolic disorders of impaired glucose tolerance causing hyperglycemia, as well as abnormal and and protein metabolism.

Which cells in the pancreas make insulin?
beta cells (in the islets of Langerhans)

What is amylin?
a substance normally secreted with insulin by beta cells
in diabetes it accumulates around beta cell membranes and converts to amyloid

What happens to the beta cells when they are dying?
amyloid deposition

Which cells make glucagon?
alpha cells

Which cells make somatostatin?
delta cells

What does somatostatin do to the alpha and beta cells?
inhibits them (and all gut neuropeptides)

What are the three major complications of diabetes?
renal disease
blindness before age 70
gangrene of the feet

What is the leading cause of blindness after the age 70?
macular degeneration

Can you diagnose diabetes from looking in the eyes?
yes, retinopathy is diagnostic

What are the two types of retinopathy?
nonproliferative and proliferatives (neovascularization)

What will you see on the retina in a nonproliferative case?
microaneurysms (earliest sign)
venous dilation
exudates
edema
capillar thickening

What happens to the disk to cup ratio with glaucoma?
the disk gets much larger and fills the cup, so the fraction gets larger

What other pathology of the eye is common in diabetics?
cataracts

What's the risk of DM for Americans born in the year 2000?
1 in 3 for men, 2 in 5 for women

What insulin independent transporter carries glucose into beta cells?
GLUT-2

What happens to the glucose once it's in a beta cell?
GLUT-2 tranports it to the mitochondria where ATP activates depolarization of the membrane
Calcium flows in-->release of stored insulin granules

What do beta cells do if hyperglycemia persists?
make more insulin

What activities does insulin cause in the body? (6)
1) transmembrane transport of glucose and amino acids
2) glycogen formation in liver and skeletal muscle
3) production of triglycerides from glucose
4) nucleic acid synthesis
5) protein synthesis
6) lypogenesis by adipose tissue
7) increases cancer growth

I just had the a-ha that perhaps hyperinsulinemia is a major reason for hypertriglyceridemia.

When insulin binds to a receptor on a target cell, what happens to GLUT-4?
it translocates to the cell membrane

What are four hormones that can induce hyperglycemia?
cortisol, catecholamines, thyroxine, glucagon

Why is IDDM now mainly just called Type I Diabetes Mellitus?
because there are others out there who are insulin dependent
because onset can happen later than childhood

What is insulitis?
an auto-immune reaction to one's own islet cell antigens

What are ICA?
islet cell antibodies

What immunoglobulin is present in 90% of type 1 pts?
IgG islet cell antibody

What other auto-immune disorders are found in 10% of type 1 diabetics?
Graves, Addison, thyroiditis, pernicious anemia

Since 1960, how much has the incidence of type 1 increased in the US and western Europe?
3x

What are the sx of type I diabetes?
3P's, ketoacidosis, low serum insulin, high serum and urinary glucose
infections
gallstones
altered platelets (increasing aggregation, clotting)
copmlications of pregnancy
xanthomas
fatty liver (NASH)
necrobiosis lipoidica, ulcers, gangrene

What viruses may trigger the autoimmune reaction causing type I diabetes?
measles
mumps
hepatitis
congenital rubella
EBV
coxsackie B
cytomegalovirus

What chemical toxins are also suspected triggers?
pentamidine = aerosol tx for AIDS pts with pneumocystis carinii
N-nitroso compounds = in bacon? increases gastric cancer risk
vacor = rat poison

If a mother has type 1 diabetes, what should she not feed to her infant to prevent it from developing antibodies to insulin?
gluten containing grains

What food product has a 16 amino acid epitope matching insulin, and potentially causing a crossover reaction?
cow's milk--bovine serum albumin has the epitope

What nutrients are essential for insulin metabolism?
zinc, magnesium, potassium

What nutrients are needed to make glucose tolerance factor?
cromium and niacin

What is glucose tolerance factor?
answer not in SSL's notes
chromodulin = a trivalent chromium-containing molecule which may enhance insulin utilization
other sources say it definitely does this and lots of other things

When glucose attaches to proteins in the body, is it reversible?
at first, yes, later, no-->AGEs = advanced glycosylation end products affecting organs

How do you measure AGEs?
measuring HGB A1C
hemoglobin gets crosslinked with sugars
under 7 is OK
under 5 is better: not diabetic

What else is causes by glycosylation in the body?
collagen cross linking
traps LDL in vessel walls-->atherosclerosis
binds to basement membranes in capillaries-->microangiopathy
binds to receptor sites on endothelial cells
causes WBC's to increase production of cytokines and growth factors
increases permeability, ECM formation, and coagulability
disturbs polyol pathways

What happens when polyol pathways are disturbed?
tissues independent of insulin develop high intracellular glucose
glucose is converted to sorbitol, then to fructose
these raise osmolarity causing injury

What tissues are not dependent on insulin for glucose uptake?
liver, kidney, retina

How does ketoacidosis develop?
when a pt has low blood sugar and low insulin, they still have glucagon
so adipose is broken down to make sugar
lipolysis generates ketones which are toxic to the brain???

What are the sx of ketoacidosis?
early you have weight loss and the 3 P's
later nausea, vomiting, tachylpena, dehydration, abdominal pain

What are the 3 P's?
polyphagia
polyuria
polydipsia

Why don't type II diabetics get ketoacidosis as often as type I?
because they have high insulin and low glucagon
don't break down fats to generate ketones

What are more of the complications of diabetes?
hypertension
hyperlipidemia, lowered HDL, high LDL and TG's-->atherosclerosis
increased platelet adhesiveness
endothelial dysfunction
glomerulosclerosis
increased risk of renal infection: pyelonephritis
necrobiosis lipoidica diabeticorum = shiny red rash with wavy border =
microangiopathic pre-tibial telangiectatic skin lesion
microangiopathy also in skeletal muscle, retina, renal glomeruli and tubules-->leak protein
stocking-glove neuropathy
gangrene with clean ulcers on bottoms of feet
gastrophoresis
autonomic neuropathy--> incontinence, diarrhea, constipation
retinopathy
cataracts
glaucoma

What macroscopic changes happen in IDDM skin?
necrobiosis lipoidica diabeticorum

How much protein in a UA counts as albuminuria?
>300/24 hours

Why do you ask for you microalbuminuria test?
because <300 doesn't show up on the regular UA

What causes gastroparesis?
glycosylation of the vagus nerve

What are the early signs of peripheral neuropathy?
burning sensation, later becomes shocking pain, numbness, tingling, cramping

Besides gastroparesis, what are some signs of autonomic neuropathy?
neurogenic bladder (stress incontinence, retention, enuresis)
erectile dysfunction (both genders)
intestinal perstalsis changes (diarrhea, constipation)

What happens to the infants of diabetic mothers whose blood sugar is poorly controlled?
their pancreas grows more and bigger beta cells, trying to process all the glucose
they grow very large using all that fuel, are hard to birth the old fashioned way
12 pounders with large heads-->C-section

What's the quickest way to get rid of type II diabetes in a 400 pound patient?
bariatric surgery, not that he recommends it

How much insulin does a normal person need when the are either exercising or fasting?
almost none

What is C-peptide?
the other half of the protein that is cleaved to make insulin

Why do you test for it?
to find how how much insulin is being made
esp in a person who is taking exogenous insulin

Why is it more accurate to test C-peptide than insulin for insulin deficiency?
because it degrades more slowly and is not used up

What is the honeymoon period in type I diabetes?
the 1st 12-18 months of treatment, when the pancreas is still producing some insulin
later on, after self-administering insulin for a while, the patient becomes insulin resistant

What are the factors involved in metabolic syndrome?
hypertension (over 130/85)
insulin resistance-->hyperinsulinemia
increased uric acid
hyperglycemia
central obesity
NASH, most common etio of elevated transaminases >35 in female, >40 in male
elevated cortisol
hyperlipidemia, TG's over 150 mg/dl, HDL under 40 men under 50 women

What percentage of Americans are type 2 diabetics?
4-8%

What's the concordance in identical twins for type 2?
50-90%

What adipokines are released by adipocytes in insulin resistance?
leptin, adiponectin, resistin

What does leptin do?
regulates appetite (-->satiety) and metabolism
downregulated by melatonin at night
regulates fertility
improves insulin sensitivity

Where does leptin come from?
produced mainly by white adipose tissue
also: brown adipose tissue, placenta, ovaries, skeletal muscle, stomach (lower part of fundic glands), mammary epithelial cells, bone marrow, pituitary and liver

Who gets leptin resistant?
obese people

more on leptin from wikipedia on 5/27/09:

In addition to being a biomarker for body fat, serum leptin levels also reflect individual energy balance. Several studies have shown that fasting or following a very low calorie diet (VLCD) lowers leptin levels.[6] It might be that on short term leptin is an indicator of energy balance. This system is more sensitive to starvation than to overfeeding.[7] That is, leptin levels do not rise extensively after overfeeding. It might be that the dynamics of leptin due to an acute change in energy balance are related to appetite and eventually to food intake. Although this is a new hypothesis, there is already some data that supports it.[8][9]

There is some controversy regarding the regulation of leptin by melatonin during the night. One research group suggested that increased levels of melatonin caused a downregulation of leptin.[10] However, in 2004, Brazilian researchers found that in the presence of insulin, "melatonin interacts with insulin and upregulates insulin-stimulated leptin expression", therefore causing a decrease in appetite whilst sleeping.[11]

Professor Cappuccio of the University of Warwick has recently discovered that short sleep duration may lead to obesity through an increase of appetite via hormonal changes. Lack of sleep produces higher than normal levels of ghrelin, a hormone that stimulates appetite by lowering leptin levels.

What does adiponectin do?
insulin sensitizing
increases with weight loss, fatty acid catabolism and low MI risk
decreases with obesity and diabetes
levels correlate inversely with BMI

Which gender has higher levels of adiponectin?
females

What does resistin do?
antagonizes insulin's effects
correlated with inflammation
predictive of coronary atherosclerosis in humans independent of CRP

Which adipokines are insulin sensitizing?
leptin and adiponectin

Which adipokine works against insulin?
resistin

If a person can be type II diabetic with a high normal fasting blood sugar, how do you test to know for sure their status?
oral glucose tolerance test, and include an insulin test too

What's a normal fasting insulin level?
3-4

How much insulin is too much?
10

How much is pathological?
22+

If a person's insulin is between 60 and 100 at 2-3 hours post prandial, what's their status?
insulin resistant

If a person has anxiety attacks, what condition should be in your differential?
hyperinsulinemia-->sudden hypoglycemia

What are some of SSL's treatment for anxiety attacks?
biotin, GABA, other B vitamins

What are some drugs that can encourage or cause type 2 diabetes?
glucocorticoids
thiazides, loop diuretics
lithium (in big doses used for bipolar)
phenothiazides (for nausea, cause dyskinesia)
phenytoin (old school anti-siezure med)
tricyclic antidepressants (now used for fibromyalgia)
indomethacin (pain killer)
oral contraceptives
total parenteral nutrition

What happens to normal gut flora when a pt is on total parenteral nutrition?
the pt is being fed by IV and gut flora are starving so they turn invasive

What mineral deficiency can cause insulin resistance all by itself?
magnesium!!!

What % of pregnant women experience gestational diabetes?
2-14%

What are some risk factors for gestational diabetes?
family hx of DM
hx of stillbirth or spontaneous abortion
hx of fetal anomalies in previous preg
obesity
advanced maternal age
5+ gravida
previous large or heavy for dates infants
Describe type 1.5 diabetes, aka LADA?
onset after age 25
initially responds to diet
looks like type 2 wihtout insulin resistance
pts are not obese
+ ICA
low C-peptide
family Hx of DM 2

According to Louise Hay, what unresolved emotions are connected with type 2 DM?
longing for what might have been
need to control
deep sorrow--no sweetness left
"issues in the tissues"

What affirmation does Hay suggest for diabetics?
"this moment is filled with joy. I now choose to experience the sweetness of today."

What are some of the effects of high fructose corn syrup that influence diabetes?
increases hepatic triglyceride synthesis
may decrease leptin synthesis
increases de novo lipogenesis
increases atherogenic lipoprotein particles (LDL)
volume: average north americans (Canadians not exempt) said to consume 63 lbs/year

According to the Nurse's Health Study, what is the risk of one soda per day?
doubles diabetes risk in women
increases wt gain in women and children

What surprise country has the highest rate of type I diabetes?
Finnland ???

What three countries have the highest numbers of diabetics?
India, China and the US

What racial group in North America has the highest risk of diabetes?
natives

What infections are especially common in folks with type 2 DM?
candidiasis, esp of the intestines

Name the "dirty neck" rash that may appear on youngsters with high blood sugar.
acanthosis nigricans

What populations with type 2 DM are more likely to experience ketoacidosis?
black adolescents & adults
native American males who drink and are thin

What is MODY?
maturity onset diabetes of the young
autosomal dominant disruption of insulin production
onset before age 25
no obesity
no insulin resistance (not type 2)
ICA negative (not type 1 or 1.5)

How many types of MODY are there?
six but I have no idea what they are
one is a transcription factor gene that's wrong
another is an enzyme mutation: glucokinase

MODY is associated with what disease of the kidneys?
cystic kidney dz

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