Case 6 - uncontrolled T2DM

Question 1

describe the role of insulin in the metabolism of the three macronutrients

Answer 1

1. glucose
   
   1. glucose is absorbed through the pancreatic cells and taken up by cells
2. fat
   
   1. insulin stimulates LPL, breaking down VLDL and chylomicrons into free fatty acids and glycerol
3. protein
   
   1. this is broken down in the absence of insulin

Question 2

indicate how endogenous and exogenous triglycerides aretransported through the bloodstream

Answer 2

1. after digestion
   
   1. exogenous triglycerides are carried by chylomicrons to muscl and adipose tissues
      
      1. these also have
         
         1. dietary cholesterol
         2. fat soluble viramins
2. when released from liver
   
   1. endogenous triglycerides are carried by VLDL from the liver to peripheral tissues. Also carry some fat soluble vitamins
      
      1. VLDL->IDL->liver or LDL->HDL

Question 3

describe the process by which endogenous and exogenous triglycerides are cleared from the bloodstream indicating the enzymes involved and their regulation

Answer 3

• endogenous
  
  • VLDL triglycerides are degraded by LPL, forming IDL
  • IDL is either endocytosed by the liver through RME or further digested by hepatic triacylglycerol lipase(HTGL) to form LDL
  • LDL can also be taken up by MO via a scavenger method
• exogenous
  
  • chylomicrons are synthesized in intestinal epithelial cells, secreted into lymph and passed into circulation, then interact with LPL.
  • LPL is activated by ApoC2, co-factor, which digests the triglycerides of chylomicrons to fatty acid and glycerol.

Question 4

Explain how uncontrolled diabetes results in accumulation of triglycerides

Answer 4

1. long-term complications
   
   1. heart disease attributed by
      
      1. dyslipidemia
         
         1. elevation of triglycerides and depressiong of HDL
   2. Fat
      
      1. absence of insulin->no stimulation of LPL. Leading to a decrease of the uptake in fatty acids and accumulation of chylomicrons and VLDL
      2. absence of insulin also leads to increasd breakdown of triglycerides in adipose tisse (hormone sensitive lipase is activated by glucogon) leading to the formation of ketone bodies.
         
         1. may be the source of keoacidosis in T1DM

Question 5

cire the consequences of hyperlipidemia and hyperglycemia on the function of the organs of the body

Answer 5

1. clinical presentations
   
   1. VLDL high
   2. chylomicrons high
   3. triglycerides high
   4. HDL low
   5. LDL high
   6. leading to microvascualr and macrovascualr dysfunction
2. nature of diabetes
   
   1. people with diagetes either don’t produce insulin or cannot use insulin effectively.
   2. w/o insulin glucose accumulates causing hyperglycemia along with lipid metaboites causing hyperlipidemia

Question 6

Provide long-term managment options for diabetes to prevent organ damage

Answer 6

• heathly diet
• physical activity
• adequate dosage and timely intake of hypoglycemic agents (T2DM)
• ensure adequate insulin

Question 7

What is the BMI of the patient?

236lbs

5’6”

Answer 7

(236/4356)*703=38.1

trick is to use (inches)^2

Question 8

what enzyme deficiencies can lead to hypertriglyceridemia?

Answer 8

• LPL deficiency
  
  • LPL is on the capillary wall of adipose and skeletal muscle. digests chylomicrons and VLDL->free fatty acids and IDL(respectivly)
• ApoC2 deficiency
  
  • cofactor for LPL

Question 9

what hormone deficiency can lead to hypertriglyceridemia?

Answer 9

insulin->low LPL activity-> impaired chylomicron and VLDL degradation->accumulation of TG.

with plenty of glucose in the bloodstream and now receptors on the surface the body calls for more fat degradation and gluconeogenesis

Question 10

what is the mechanism of action of insulin on the clearance of TG from the bloodstream?

Answer 10

1. insulin stimulates synthesis of LPL, which increases TG degradation int FAs and glycerol

Question 11

what do increase levels of amylase, pancreatic lipase and trypsin indicate?

Answer 11

damage to pancreatic acinar cells and acute pancreatitis

elevated serum levels of trypsin indicate ischemia and acidosis due to hypertriglyceridemia and activation of trypsinogen. Acidity is from CO build up

Question 12

how does the activation of trypsinogen contribute to damage to teh pancras?

Answer 12

activation of trypsinogen leads to trypsin->protein breakdown->damage of acinar cells->acute pancreatitis. Trypsin in pancreatic cells weaken vesicles containing cathepsin(major lysosomal protease) which are releasd into cytosol causing acinar cell death

Question 13

would excessive release of pancreatic lipases contribute to acute pancreatitis?

Answer 13

pancreatic lipases digest lipids in cell walls of pancratic cells, also digests chylomicrons and VLDLs->leads to free fatty acids->leads to inflammatory mediators->futher damage to pancrease ->acut pancreatitis

free fatty acids lead to inflammation?

Question 14

what are the possible mechanisms of pancreatic damabe in the presence of excess TG carrying lipoprotiens?

Answer 14

accumulation of chylomicrons and VLDL can lead to blockage of pancreatic capillaries->impaired blood flow->signal for inflammation

Question 15

why was the pregnancy test conducted?

Answer 15

hypertriglyceridemia may also occur in some pregnant women as a result of altered hormone levels that trigger elevations in serum cholesterol and TG. could lead to complication for mother and fetus

Question 16

why was the temperature slightly elevated?

Answer 16

factor that influence BEE lead to an increase in basal temperature.

increase in 7%BEE->increase 1degree F

Question 17

why was c-reactive protein measured?

Answer 17

c-reactive protein is an early indicator of infectious or inflammatory conditions. Acut pancreatits is characterized by inflammation of the pancreas, leading to elevated C-reactive protein levels

Question 18

Why is blood pH abnormal?

Answer 18

1. w/o insulin, cells are starved of glucose ->leads to glucagon release ->activating hormone sensitive lipase ->FA release ->Ketone body production ->metabolic acidosis
2. ischemia of pancreatic cells ->build up of CO2 ->H2CO3 ->H + HCO3- ->decrease in pH

Question 19

why were there ketones in the urine?

Answer 19

hormone sensitive lipase releases FA->excess FA travel to liver ->beta oxidation->ketone body synthesis

Question 20

Is the presence of ketone bodies a normal finding in T2DM?

Answer 20

NO!!!

ketone bodies are characteristic of T1DM. Ketones bodies only found in T2DM in the presence of illness

for this patient it was the presence of acute pancreatitis

Question 21

Why are BUN and creatinine high in serum?

Answer 21

1. muscle insensitivity to insulin ->impaired glucose uptake ->protein breakdown -> increased BUN
2. excess glucose-> sorbitol formation ->kidney damage ->elevated creatinine

Question 22

why did Apo C2 and insulin have to be adminstered at the same time?

Answer 22

insulin activates lipoprotein lipase (LPL), the co-factor for LPL is ApoC2

Question 23

why did Dr.K advise the patient to limit her intake of fat to medium-chain fatty acids?

Answer 23

• Medium chain triglylcerides are an option to treat sever hypertriglyceridemia by preventing postprandial chylomicronemia
• Mechanism
  
  • MCT treatment used MCT binding to albumin for circulation and transport to the liver where they can be oxidized to ketones, therby avoiding lipid synthesis
  • MCFA are not packaged in chylomicrons -> leads to decreased amount of chylomicrons->decreased capillary plugging and decreased hypertriglyceridemia

Question 24

How does gemfibrozil work?

Answer 24

induces LPL, acting as atype of regulator

1. increasing LPL activity
2. inhibiting the synthesis of apolipoprotein B and asissting with its clearance
   
   1. a carrier molecule for VLDL,