What is the diagnostic test for acromegally (gold standard)?

• Glucose load test where you give glucose and 1 hour later the GH should be < 1ng/ml.
• Remember GH is a counter regulator hormone to insulin in that GH encourages high blood glucose (and it would be stupid to turn insulin at the same time cause it has the opposite effect!)
• It is the hyperglycemia that turns down GH production

How does blocking the pituitary stalk affect PRL secretion? What about antipsychotic drugs?

• Hypothalamus's role is to inhibit PRL secretion and it does that by sending dopamine to the pituitary to inhibit PRL release.
• A lot of those drugs decrease dopamine, which will decrease the hypothalmus's ability to shut off PRL secretion

What mechanisms encourage renin release?

• Baroreceptors: in the renal afferent arterioles (decrease in stretch receptors causes increase in renin release)
• SNS: Beta 1 stim in JG cells stimulates renin release. (central barorecepros or intrarenal baroreceptos stimulate the SNS)
• Macula densa: if it doesn't see enough salt, then it figures that the GFR is low (cause all that salt gets sucked up in the PCT) and so tries to increase GFR by nudging the JG cells to release renin.

What stimulates aldosterone secretion from the adrenal cortex? What zone makes it?

• ACTH
• Hyperkalemia
• decreased renal afferent arteriole HP
• SNS

How do you screen for Cushings, and what test would you do to diagnose it.

How would you differentiate between 1 and 2 adrenal insufficiency?

• Give ACTH, then if the adrenals respond by producing cortisol, it was secondary. If they dont respond and cortisol is still low cause the adrenals are screwed up, it's primary.

How would you diagnose a pheo?

• Clinical triad is a big indicator:

What are the diagnostic criteria for metabolic syndome?

A diagnosis can be made when an individual has 3 or more of the following risk factors:

·       Fasting plasma glucose (FPG) ≥ 6.1 mmol/L

·       Blood pressure ≥ 130/85 mm Hg

·       Triglycerides ≥ 1.7 mmol/L

·       HDL-C

-        Men: < 1 mmol/L

-        Women: < 1.3 mmol/L

·       Abdominal obesity (waist circumference)

-        Men: > 102 cm

-        Women > 88 cm

What are the normal values for glucose?

• Fasting glucose: 4-6 mmol/L
• 2 hour post-prandial: 5-8 mmol/L

What is the diagnostic critera for DM, is it the same for type 1 and type 2?

*It is the same for both types, and you can have either one of these three:

• Random blood sugar > 11.1 mmol/L plus symptoms
• Fasting blood glucose > 7mmol/L (not eaten anything for at least 8 hours)
• Oral glucose tolerance test (2 hrs post 75 g glucose) > 11.1

HbA1c

• That is the percentage of RBCs that are glycosylated and represents blood sugar control for the past 3 mo or so (cause that's how long RBCs live for)
• Normal non DM amount is 4-6%

What drug would you give for:

- increased insulin secretion

- decreased hepatic glucose output

- limit starch digestion/absorption

- increase insulin sensitivity

- Glyburide (others are glipizide, glimiperide and tolazamide)

- Metformin (others are pioglitazone, rosiglitazone)

- Acarbose or miglitol

- Pioglitazone or rosiglitazone

*metformin is given often as a insulin sensitizer and it does work that way on the liver

What does lipoprotein lipase do?

• It breaks down triglycerides in Chilomicrons, VLDLs and IDLs in order to release free fatty acids so that they can be stored in adipost tissue, go to the liver to get put into VLDLs, or to get taken up by peripheral cells like muscle
• This enzyme is found in adipose and muscle tissue
• Then the chilomicron remnants, IDLs and LDLs bring the cholesterol back to the liver

The liver takes all of the cholesterol "left over" from the lipoproteins after they've delivered their triglycerides and some choesterol to the body's cells. What does the liver do with all that cholesterol?

• It breaks it down into bile or bile acids, 50% of bile and 97% of bile acids are reabsorbed (this is called enterohepatic circulation)
• It can also be put back out into the blood in VLDLs

Lipoprotein Lipase (LPL)

o   Expression: Adipocytes and smooth muscle cells

o   Translocation: Functional on endothelial surface

o   Function: Hydrolyzes TGs from CM and VLDL. Apo CII is a cofactor

o   Products: Free Fatty Acids

o   Regulation: Fasting and insulin increase LPL Synthesis

o   Deficiency: Genetic LPL deficiency associated with high CM

 Lecithin Cholesterol Acyltransferase (LCAT)

o   Expression: Hepatocytes

o   Function: LCAT mediates cholesterol and phospholipids transfer from TG rich lipoproteins to HDL and formation of Cholesterol esters in HDL

o   Regulation: LCAT is activated by HDL and Apo AI

o   Deficiency: Genetic LCAT deficiency is associated with absence or decreased levels of HDL and corneal opacity

HMG-CoA reductase

• this is the enzyme that catalyses the formation of cholesterol
• this is where statins work to decrease the amount of cholesterol produced
• because there is less cholesterol, cells with upregulate their number of LDL receptors, thus taking more LDLs out of circulation.

What is the only lipoprotein with apolipoprotein B48?

• Chilomicrons cause those come from the intestine and that's where ApoB48 is made
• ApoB48 will not be found in a fasting state

How are chilomicron remnants cleared?

• By the liver
• they are taken up by LDL receptors and chilomicron remnant receptors (LRP = remnant receptors)
• Clearance is Apo-E mediated

What is the only Apo on LDLs?

• Apo B100
• This is a ligand for the LDL receptor
• VLDLs and IDLs also have ApoB100, so can also be cleared by liver LDL receptors
• People with familial defective apoB100 have big problems clearing their LDLs and have them in excess

What is ApoE?

• It's an Apo on VLDLs, IDLs, CMs, remnant CMs and some HDLs

LDL receptor

• The LDL receptor will bind any lipoproteins with either ApoB (so LDLs) or ApoE (all the others) *Note that VLDLs and IDLs have ApoB also
• these are present on all cells, not just hepatic cells
• the number of LDL receptors on a given cell memrane will depend on the cell's need for cholesterol

-       Hepatic Lipase (HL)

o   Expression: Hepatocytes and macrophages

o   Function: Hydrolyzes Gs and phospholipids in HDL to generate lipid poor, small disc shaped HDL. Mediates transformation of VLDL to IDL and LDL and the uptake of LDL

o   Regulation: Oestrogen lowers HL activity in vitro

o   Deficiency: Characterised by increased HDL-TG and other types of TG rich lipoproteins

What are the primary and secondary disorders associated with high cholesterol only?

Primary:

-familial hypercholesterolemia: mutations in LDL receptor, most patients are heterozygous, tendon xanthomas, xanthalasmas (eye deposits), arcus cornae at under 40 years old. Homozygous people get tuberous xanthomas

-familial defective apoB100: can still clear everything but LDLs with ApoE, but phenotypically similar to FH (above). Less severe

*Both have increased early risk for CVD

Secondary:

-hypothyroidism

-nephrotic syndrome

-anorexia nervosa

What are the primary and secondary disorders associated with both high cholesterol and high triglycerides?

-Familial combined hyperlipidemia: overlaps with metabolic syndrome, phenotype may vary from and within individuals, increased CVD,         NO XANTHOMAS!!

-Familial dysbetalipoproteinemia: impaired binding of ApoE (LDLs can still bind through their ApoB100 but CM remnants and IDLs are screwed) PALMAR XANTHOMAS

Secondary: DM, nephrotic syndrome, hypothyroidism

What are the primary and secondary causes of disorders of increased TGs?

-LPL deficiency: very high TGs, abdominal pain, pancreatitis, autosomal recessive, eruptive xanthomas, lipemia retinalis, plasma is super lipemic (sooooo gross!!) Treat mostly by limiting fat intake.

-ApoCII deficiency: autosomal recessive, similar to LPL def

Secondary: obesity, estrogen/OCPs/preg, DM, HIV meds, uremia, GCs/Cushings and acromegally

When do you consider treating someone for a lipid problem?

What are your treatment targets when you're treating hyperlipidemia?

• For high and moderate risk you want the LDL to be <2mmol/L or at least a 50% reduction in LDL OR ApoB < 0.08g/L
• For low risk you just look for that 50% decrease in LDL

Niacin

- vitamin B3, nictotinic acid (not nicotinamide)

-↓ VLDL production by the liver, ↑ VLDL clearance, ↓ TGs and ↑ HDLs

-limited use due to side effects:

Pruritis, skin flushing, hepatotoxic, glucose intolerance, vision problems, exacerbation of peptic ulcer (so a lot of random stuff)

Fibrates

- Gemfibrozil, fenofibrate

- does not alter LDL levels

- ↓ TGs and ↑ HDLs

- decreased VLDL production and increased clearance (exaclty like niacin!)

- Still lots of adverse effects:

Flu like (muscle cramps, tenderness, stiff, weak), bile disease, makes anticoagulants and hyoglycemic agents stronger

Bile acid binding resins

- effective with statins or niacin in people with very high LDLs (otherwise can be used on it's own)

- prevents reabsorption of bile acids

- adverse effects:

lower fat soluble vitamin absorption, may increase VLDL levels, nausea, constipation, bloating (remember these cause these are gut symptoms), may interfere with absorption of other drugs, doesn't taste good. 

Statins

- HMGCoA reductase inhibitors (that's the enzyme that forms cholesterol)

- first choice drug for those with CHD risk

- brings down LDLs and also TGs

Adverse effects:

Generally well tolerated, myalgia, muscle weakness, first pass metabolism is CYP3A4, and grapefruit juice is an inhibitor of that so watch out

Cholesterol absorption inhibitors

- work at intestinal brush border

- no effect on fat soluble vitamins or triglycerides

- use in combo with statin

Adverse effects:

myalgia, hepatic...

What would be a pretty good combination of lipidemia drugs?

• Statin and bile acid sequestrant (cause for the second one you would get an endogenous increase in cholesterol synthesis to compensate, so you cna dial down that compensation with a statin).

LDL-C

LDL = total ch – (HDLch + 0.45TG)

Describe 2 hormone changes that will bring down the ApoBE receptor action?

- Remember ApoBE is the LDL receptor

- We see downregulation when there is decreased estrogen and when there is decreased thyroid hormone

What are the diagnostic criteria for DKA?

• high glucose (>14 mmol/L)
• ketones in plasma
• increased AG metabolic acidosis
• bicarb lower than 15
• low pH

Describe some signs of DKA

What's the treatment for DKA and what do you need to be careful about in treating it?

- First, give insulin but monitor the K levels so that it does not go too low. Add glucose to IV when blood glucose gets to about 12-14 mmol/L.

- Give saline and fluid replacement (you will loose fluid cause of osmotic diuresis of such high plasma glucose)

- only treat with bicarb if they go down really low (like pH 6.95 and less)

Describe 3 counter-regulatory hormones to insulin

• Glucagon
• GH
• Epinephrine
• Cortisol
• (oh look that's 4..)