Term
What is the difference:
GLUT 2 vs. GLUT 4 |
|
Definition
GLUT 2
where: beta cells of pancreas, liver, brain, intestines
what: to sense glucose levels in pancreas
GLUT 4
where: adipose tissue, muscle
what: insulin-sensitive |
|
|
Term
How does insulin affect each of the following:
- Liver glucokinase
- Liver PEPCK
- Carnitine acyl transferase
- Adipose and muscle GLUT4
- Triglyceride lipase |
|
Definition
increases glucokinase --> increase glycogenolysis
decreases PEPCK --> inhibit gluconeogenesis
decrease carnitine acyl transferase --> inhibit ketogenesis
increase GLUT 4 --> take glucose into cells
decrease triglyceride lipase --> decrease lipolysis |
|
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Term
| Describe Insulin production / storage. |
|
Definition
beta cells in islets of langerhans:
Preproinsulin ---(rEr)--→ proinsulin --(endopeptidase)--→ insulin
Insulin(A and B chain)
Proinsulin (A, B and C chain)
Preproinsulin has a signal sequence too
Stored as an inactive hexamer in granules. Monomer is active with a half life of 4-6 minutes, mostly degraded after one hour. |
|
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Term
| What are the two phases of insulin secretion? |
|
Definition
Secreted in 2 phases
1. Granule release, insulin dependent
glucose enters via GLUT 2 → increased ATP and decreased ADP → inhibits K-ATP channels → depolarization of cell → activates L-type voltage gated Ca channels → increase intracellular Ca → insulin granule release
2. Sustained slow release, insulin independent |
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Term
|
Definition
| secreted with insulin (1:100), a peptide hormone that suppresses post-prandial glucose, suppresses food intake, slows gastric emptying = makes you feel full! |
|
|
Term
Differentiate pathogenesis of:
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Central Diabetes Insipidus
Nephrogenic Diabetes Insipidus |
|
Definition
Type 1 Diabetes Mellitus
-autoimmune destruction of islet beta cells resulting in no insulin production
-aka. "juvenile onset diabetes"
-more ketosis prone
Type 2 Diabetes Mellitus
- insulin resistance, beta cells can't produce enough insulin to overcome the insulin resistance in the body, so you don't get the effects of insulin
- mutations in insulin receptor, glucokinase (HNF), or mutations that reduce beta cell function
Central Diabetes Insipidus
Nephrogenic Diabetes Insipidus |
|
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Term
| Symptoms of Type 1 Diabetes |
|
Definition
3 P's : Polyuria, polydipsia, polyphagia (less typical)
weight loss
fatigue
blurred vision
dry mouth and skin
poor wound healing
impotence (wah-wah)
*fruity/nailpolish breath odor, metabolic acidosis, compensatory tachypnea if ketotic |
|
|
Term
| Lab values associated with Type 1 Diabetes Mellitus. |
|
Definition
positive anti-GAD65 Ab
high urine specific gravity
BUN Cr ratio over 20:1 from hypovolemic dehydration
low pH in blood if DKA |
|
|
Term
| Complications of Type 1 DM. |
|
Definition
hyperglycemia
massive polyuria
dehydration
electrolyte shifts
ketosis
acidosis with elevated anion gap
pseudohyponatremia
elevated potassium
elevated phosphate
microvascular dz (retinopathy, nephropathy, neuropathy)
macrovascular dz --> HTN |
|
|
Term
| Pathogenesis of Microvascular dz and Macrovascular dz in Diabetes Mellitus |
|
Definition
microvascular disease in insulin independent tissue (bc they take in the super high sugar --> osmotic cellular injury)
retinopathy
nephropathy
neuropathy
macrovascular disease from glucose sticking to RBCs and crosslinking to collagen
stiff arteries, atherogenesis
ischemic heart dz, stroke
high LDL
HTN
kidney dz |
|
|
Term
| Risk factors for Type 1 DM |
|
Definition
Family history
DR 3 or 4 HLA genotype (10x risk)
Caucasian
Northern European (cold climate)
Age 4-6 and 10-14
** HLA DR2 is protective |
|
|
Term
| Complications of Type 2 DM |
|
Definition
blindness
kidney failure
stroke
heart attack
leg amputation
* lose 11 years of life if diagnosed at age 50 |
|
|
Term
| Risk factors for Type 2 DM |
|
Definition
being born (30% chance of Type 2 DM)
aging
Pima Indians and every race except caucasians
obesity
sedentary lifestyle
high glycemic index foods
high saturated fat and transfat (bc increases insulin resistance) |
|
|
Term
| How does obesity and FFA increase risk of Type 2 DM? |
|
Definition
| obesity releases more free fatty acids (FFA) into the bloodstream, which increase TG uptake and deposition in skeletal muscle and liver, and therefore promote insulin resistance |
|
|
Term
| How does exercise decrease type 2 DM? |
|
Definition
| Exercise increases the number of glucose transporters in skeletal muscle, which increases insulin sensitivity. |
|
|
Term
| What do you SEE in diabetic nephropathy? |
|
Definition
Kimmelstiel-Wilson lesion
Thickened BM
Granular surface of Kidney
Pitting in kidney surface from arterial sclerosis |
|
|
Term
| What do you SEE in diabetic retinopathy? |
|
Definition
Retinal detachment
Thickened BM
Microaneurysms and abnormal retinal vessels
Macular Edema and lipid exudate
Neoangiogenesis and hemorrhage that begins peripherally |
|
|
Term
| What do you SEE in diabetic Neuropathy? |
|
Definition
Segmental demyelination
Thickened BM
Ulcers (with peripheral artery disease) |
|
|
Term
| List Microvascular vs Macrovascular complications of diabetes |
|
Definition
Microvascular
Nephropathy (glomerulonephritis)
Retinopathy (cataracts, detachment)
Neuropathy (ulcers. distal symmetric sensory or sensorimotor)
Skin and muscle infections
Macrovascular
Coronary artery disease (MIs)
Cerebrovascular disease (strokes)
Peripheral artery disease (ulcers, gangrene, amputation)
Arteriosclerosis (HTN) |
|
|
Term
| What is the "beta cell rest" hypothesis? |
|
Definition
| achieving normal glucose levels in pre-diabetics lowers the risk of progressing to full blown diabetes |
|
|
Term
What is the major marker for microvascular risk?
for macrovascular risk? |
|
Definition
microvascular risk - HA1C
macrovascular risk - blood glucose
(correlates with cardiovascular risk) |
|
|
Term
|
Definition
| Short acting insulin. Onset 15-30min, peak 1-2 hrs. |
|
|
Term
|
Definition
| Short acting insulin. Onset 15-30min, peak 1-2 hrs. |
|
|
Term
|
Definition
| Short acting insulin. Onset 15-30min, peak 1-2 hrs. |
|
|
Term
|
Definition
Intermediate-long acting insulin. Onset 1-4 hrs, peak 6-10 hrs.
Look for 3 am hypoglycemia. This is a risk.
Higher risk of hypoglycemia than with Glargine or any of the longer acting insulins.
Should take right before bed instead of with dinner to reduce risk of early morning hypoglycemia. |
|
|
Term
|
Definition
| Long acting insulin, lasts 14 hrs |
|
|
Term
|
Definition
| Long acting insulin, lasts 22 hrs |
|
|
Term
|
Definition
| Long acting insulin, new, the lowest rates of hypoglycemia. |
|
|
Term
|
Definition
| Short acting insulin. Onset 15-30min, peak 1-2 hrs. |
|
|
Term
| What is the basis for the different time courses of different synthetic insulins? |
|
Definition
Alterations in their affinity to zinc because inactive insulin is stored around zinc and must dissociate to become active. This affinity is based on alterations in A and B chains because synthetic insulins have no C chain, remember.
The very fast acting insulins don't even associate with zinc. |
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|
Term
| What is the "dawn phenomenon" when talking about hyperglycemia? |
|
Definition
| Growth hormone antagonizes insulin, and is secreted more at night. This means your glucose could creep up at night since your regular insulin dose is less effective. This causes morning hyperglycemia. |
|
|
Term
What are incretins?
eg. GLP-1 and GIP
GLP-1 analogues = exenatide
DPP4 inhibitors = sitagliptin |
|
Definition
Gut factors released in response to eating glucose. They are released naturally in very small amounts along with insulin after eating and basically potentiate insulins effects. They increase insulin release, decrease glucagon, decreased gastric emptying causing a feeling of satiety, decreased weight
DPP4 breaks down incretins. |
|
|
Term
| When putting a new patient on insulin, how do you find the right dose? |
|
Definition
eg. start with 10 units of long acting insulin in the evening, and increase dose by 1 unit every day until blood glucose reaches 120 mg/dL.
If blood glucose spikes after meals but gets sufficiently low in between meals, then add short acting bolus with meals:
(BG-100)/F
BG = blood glucose after meals
100 = goal blood glucose
F = insulin sensitivity factor, ranges from 10-50, tells you how strong a response the patient has to insulin. |
|
|
Term
| whicwhich is better, GLP-1 analogues (exenatide) or DPP4 inhibitors (sitaglipitin)? |
|
Definition
GLP-1 analogues (incretins) are better for HA1C, weight, beta cell mass, and reduced side effects.
DPP4 inhibitors slow your natural incretin's destruction (DPP4 breaks incretins down) |
|
|
Term
| When do you use Metformin? |
|
Definition
FIRST LINE for ALL type 2 diabetics unless contra-indicated.
Useless in type 1 |
|
|
Term
| List 4 mechanisms of why insulin resistance arises in type 2 diabetics. |
|
Definition
Post receptor defects - decreased phosphorylation downstream (therefore inefficient insulin signaling)
Mobilization of triglycerides (alt energy source) --> diacylglyceride levels rise --> increases protein kinase C epsilon and theta --> reduce insulin signaling effectiveness
FOXO-1 activation --> upregulates PEPCK and G6Phosphatase (gluconeogenesis)
*(metformin inhibits G6Phosphatase)
GLUT4 is sequestered --> less binding sites for insulin to be effective |
|
|
Term
| How does oxidative stress lead to decreased insulin secretion in Type 2 Diabetes? |
|
Definition
superoxide --> UCP2 --> no ATP synthesis --> open K-ATP channel --> no depolarization --> no insulin release
unfolded protiens --> UPR --> CHOP --> apoptosis
details:
superoxide --> increases UCP2 (uncoupling protein) --> uncouples ATP synthesis from diffusion in the ATP synthase --> low ATP --> cannot close the K-ATP channel that allows beta cell depolarization --> beta cell can't depolarize and therefore can't release insulin
oxidative stress also triggers the Unfolded Protein Response. The cell then tries to slow down translation and increase chaperone proteins. When it can't keep up it triggers apoptosis (via pro-apoptotic protien CHOP). |
|
|
Term
| What are the 5 classes of non-insulin / non-incretin treatments for Diabetes Mellitus. |
|
Definition
Sulfonylureas (SU) - Glipizide
Biguanides - Metformin, Glucophage
Glinides - Prandin, Starlix
Thiazolidinediones (TZD) - Pioglitazone, Actos
Alpha-glucosidase inhibitors - Precose, Glyset |
|
|
Term
What is the mechanism of
Sulfonylureas (SU)
eg. Glipizide |
|
Definition
Stimulates insulin secretion
Same as Glinides
detail:
bind to the K-ATP channel on beta cells so that they remain open, depolarizing the cell to trigger the insulin release |
|
|
Term
What is the mechanism of:
Biguanides
eg. Metformin, Glucophage |
|
Definition
Inhibits hepatic gluconeogenesis
Increases hepatic insulin sensitivity
therefore decreasing hepatic glucose production
detail:
decreases mitochondrial resp chain complex 1 --> decrease ATP and increase AMP --> AMPK activation --> regulates acetyl coA carboxylase, FA oxidation, hepatic lipogenesis, PEPCK/G6Pase expression |
|
|
Term
What is the mechanism of:
Glinides
eg. Prandin, Starlix |
|
Definition
Stimulate Insulin secretion
Same as SUs
detail:
Bind the K-ATPase of beta cells to increase insulin release by depolarizing the cell (open the channel) |
|
|
Term
What is the mechanism of:
Thiazolidinediones (TZD)
eg. Pioglitazone, Actos |
|
Definition
Reduce lipotoxicity
Increase muscle insulin sensitivity
Stimulate favorable fat redistribution
Suppress free fatty acid release
detail:
agonist for PPAR-gamma, which regulates genes involved in fatty acid uptake and adipocyte differentition |
|
|
Term
What is the mechanism of:
Alpha-glucosidase inhibitors
eg. Precose, Glyset |
|
Definition
Inhibit/delay glucose absorption
detail:
inhibits brush border hydrolase |
|
|
Term
Pros and Cons of:
Sulfonylureas (SU)
eg. Glipizide |
|
Definition
Pros:
cheap
Cons:
hypoglycemia
weight gain
contrainications:
renal dz
liver dz
pregnant |
|
|
Term
Pros and Cons of:
Biguanides
eg. Metformin, Glucophage |
|
Definition
Pros:
no weight gain
fine in pregnancy
Cons:
GI complaints
Rarely lactic acidosis
contrainications:
renal dz
liver dz |
|
|
Term
Pros and Cons of:
Glinides
eg. Prandin, Starlix |
|
Definition
Pros:
short acting
reduced risk of hypoglycemia
Cons:
Taken with every meal
expensive
contrainications:
renal dz
liver dz
pregnant |
|
|
Term
Pros and Cons of:
Thiazolidinediones (TZD)
eg. Pioglitazone, Actos |
|
Definition
Pros:
Pioglitazone improves lipid profile
Cons:
Fluid retention
Heart failure, rare
fracture risk
weight gain
bladder cancer risk
expensive
contrainications:
liver dz
CHF
Bladder cancer
pregnant |
|
|
Term
Pros and Cons of:
Alpha-glucosidase inhibitors
eg.Precose, Glyset |
|
Definition
pros:
no weight gain
Cons:
taken with each meal
GI complaints
expensive
contrainications:
renal dz
liver dz
GI dz
pregnant |
|
|
Term
What non-incretin/non-insulin therapy can you give to a diabetic who has:
Renal disease |
|
Definition
Can't give them anything EXCEPT
TZDs |
|
|
Term
| What non-incretin/non-insulin therapy can you give to a diabetic who has: Hepatic disease |
|
Definition
| Can't give them anything... Metformin alpha-glucosidease SUs Glinides TZDs |
|
|
Term
| What non-incretin/non-insulin therapy can you NOT give to a diabetic with Congestive Heart Failure |
|
Definition
|
|
Term
| Contraindicated diabetic non-insulin / non-incretin drug for GI disease |
|
Definition
| alpha-glucosidase inhibitors |
|
|
Term
| Contraindicated diabetic drug (noninsulin/nonincretin) for Bladder Cancer |
|
Definition
|
|
Term
| What non-incretin/non-insulin therapy can you give to a diabetic who is: Pregnant |
|
Definition
| metformin and acarbose are safe |
|
|
Term
| What are the symptoms of hypoglycemia? |
|
Definition
arterial blood glucose < 60 mg/dL
sweating
anxiety
nausea
trembling
feelings of warmth
headache
confusion
inability to concentrate
dizziness |
|
|
Term
| Causes of ketotic vs. non-ketotic hypoglycemia |
|
Definition
Ketotic (liver thinks its fasting)
- substrate limited (not enough carbs)
- hormone deficiency (cortisol, epinephrine, glucagon, hypopituitarism)
- glycogen storage dz
- gluconeogenesis disorder
- drug-induced
Non-ketotic
- too much insulin
- inable to make ketones
- inable to shuttle FAs (therefore can't make ketones) |
|
|
Term
What is PHHI?
(Persistent hyperinsulinemic hypoglycemia of infancy) |
|
Definition
a group of congenital disorders that cause non-ketotic hypoglycemia because beta cells release too much insulin
K-ATP channel mutation (SUR1 gene)
(depol more --> increase insulin release)
GDH mutation - less severe phenotype
(increase oxidation of glytamate --> increase ATP --> increase insulin release)
Glucokinase mutations - activating mutation
(very low threshold for insulin inhibition, ie always release insulin unless blood glucose is under 40 mg/dL) |
|
|
Term
Steps to evaluate a new patient with hypoglycemia.
(first 2 steps are key) |
|
Definition
1. test for ketones (urine or serum)
2. CRITICAL blood sample (red top, no additives) - run simultaneous glucose with cortisol, insulin, GH, ketones
3. might be usefule to look at electrolytes, kidney function, CBC, etc |
|
|
Term
| Treatment for hypoglycemia |
|
Definition
eat sugar!
alternatives:
D10 in neonates IV
D25 in adults IV
backup:
glucagon if seizing / unconscious
if hyperinsulinemic:
Diazoxide (prevents insulin release) |
|
|
Term
|
Definition
drug to prevent insulin release by keeping the Katp channel open (preventing depol in beta cells).
used to treat hyperinsulinemia |
|
|
Term
Does a childs BMI correlate better with:
mother or father?
biological or adopted parents? |
|
Definition
Mother > Father
Biological > Adopted parents |
|
|
Term
What is Leptin?
How does it relate to weight gain/loss? |
|
Definition
Leptin is a hormone made in adipose tissue that triggers satiety in the hypothalamus. It does this by activating the MC4R receptor.
Overweight people become leptin resistant, and therfore have high blood levels of leptin and low CNS levels of leptin.
Giving someone leptin causes weight loss (ONLY if they have abnormally low levels)
Giving leptin to someone who has normal levels of leptin won't do anything. |
|
|
Term
| How does "metabolic programming" impact weight gain/loss? |
|
Definition
Prenatal/neonatal environment impacts how your body reacts to food later in life. If the baby is starved in utero, he is programmed to hang onto all the calories he can even later in life.
Babies small for their gestational age at birth have a higher risk of becoming obese. |
|
|
Term
| What does the MC4R receptor have to do with obesity? |
|
Definition
This is the most common single gene defect in obesity (causes obesity before age 4).
The MC4R receptor signals satiety to the body. Leptin activates it. Ghrelin inhibits it. |
|
|
Term
Order these in terms of risk of obesity?
Black females
White females
White males |
|
Definition
Black female = highest risk
White female = lowest risk |
|
|
Term
| List some complications of obesity. |
|
Definition
Metabolic syndrome (Db, Htn, dyslipidemia, hyperandrogenemia in women)
Cardio: venous stasis, htn, dyslipidemia
Pulm: sleep apnea, chronic lung dz
Renal: glomerular dz
GI: GERD, steatosis hepatitis
GU: stress incontinence, hyperandrogenemia (acne, scalp hair loss, excessive body hair, high libido, irregular menstrual cycle)
Immune: fungal infections, cancer |
|
|
Term
| List 4 steps of an MD's role in managing an obese individual. |
|
Definition
1. Introduce prevention strategies
2. Diagnose cause of weight gain (lifestyle or pathologic cause?)
3. Diagnose and manage Complications of Obesity
4. Pharm / surgical management if morbidly obese |
|
|
Term
When attempting to diagnose a pathologic cause of weight gain, you look for genetic defects, drug-associated weight gain, endocrine disorders, and genetic syndromes.
What makes you think it is a genetic defect? eg's |
|
Definition
This would be a leptin signaling pathway defect with leptin, its receptor, or the MC4R receptor.
Obesity before age 4 is the key feature, though many children are obese before 4 and do not have a defect here. |
|
|
Term
When attempting to diagnose a pathologic cause of weight gain, you look for genetic defects, drug-associated weight gain, endocrine disorders, and genetic syndromes.
What makes you think it is an endocrine disorder? eg's |
|
Definition
poor linear growth despite weight gain
eg.
hypothyroidism
growth hormone deficiency
cushing syndrome
pseudohypoparathyroidism |
|
|
Term
When attempting to diagnose a pathologic cause of weight gain, you look for genetic defects, drug-associated weight gain, endocrine disorders, and genetic syndromes.
What makes you think it is a genetic syndrome? eg's |
|
Definition
developmental delay / dysmorphic features
eg.
Prader-Willi
Bardet-Biedl
Cohen
Fragile X
WAGR |
|
|
Term
| List the criteria for adolescents to qualify for bariatric surgery. |
|
Definition
BMI > 40
Comorbidity present
Skeletal maturity
Participate (be compliant) in 6 month medical weight management.
Willing to make lifestyle changes (whole family). |
|
|
Term
| Compare Restrictive and Malabsorptive bariatric surgeries. |
|
Definition
Restrictive
- reduce stomach size therefore limit caloric intake.
Malabsorptive
- remove absorptive portion of digestive tract, therefore just don't take in the calories you eat. |
|
|
Term
Compare Gastric bypass, Sleeve gastrectomy, and Adustable Gastric band.
Operation, complications, efficacy. |
|
Definition
Gastric Bypass
- most complications
- both restrictive (makes stomach smaller) and malabsorptive (bc bile and pancreatic juices downstream)
Sleeve Gastrectomy
- complications are less likely to be lethal than bypass
- remove 85% of stomach, with antrum preserved for peristalsis.
- mostly restrictive, but removes some ghrelin producing cells (which activate the MC4R receptor to increase desire to eat)
Adjustable Gastric Band
- least complications, safest
- controls satiety, purely restrictive, can adjust the band size after surgery with saline injection |
|
|
Term
| What is the difference between type A1 and A2 gestational diabetes? |
|
Definition
A1 - can be controlled by diet and exercise alone
A2- requires medical treatment |
|
|
Term
| List risk factors for gestational diabetes. |
|
Definition
family hx of diabetes
past macrosomia (big fat baby)
obese
old (>35)
complicated past pregancies
past gestational diabetes
being any race but white |
|
|
Term
| List maternal complications of gestational diabetes. |
|
Definition
htn disorder - preeclampsia, eclampsia
cesarean section
stillbirth
trauma (big fat baby...eeeee) |
|
|
Term
| List fetal complications/consequences of gestational diabetes. |
|
Definition
macrosomia (big fat baby)
hyperbilirubinemia
shoulder dyslocation
birth trauma
neonatal hypoglycemia
respiratory distress syndrome
childhood obesity
fetal hyperinsulinemia --> increased # of fetal fat cells |
|
|
Term
Should you check for diabetes after a mother who had gestational diabetes has given birth?
Explain the oral glucose tolerance test. |
|
Definition
Yes! 50% of mothers develop diabetes within 10 year of an affected pregnancy. Also 50% recurrence risk in next pregnancy.
screen mothers with a 75gr oral glucose tolerance test at 6-12 weeks after delivery.
Diabetic if:
- fasting blood glucose > 126
- 2hrs after 75g oral glucose, blood glucose is > 200 |
|
|
Term
| When / how do you check for gestational diabetes? |
|
Definition
1. screen for diabetes in prenatal visit
2. at 24-28 weeks, 75g glucose tolerance test |
|
|
Term
| What are the current guidelines for exercise in adults? |
|
Definition
aerobic exercise 150 min / week
strength training 2-3x/week
no more than 2 consecutive days without exercise |
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|
