Lecture 10 Flashcards
Phases of starvation:
1) Glycogenolytic (approx one day)
Glycogen to glucose. In muscles = for muscles, in liver = elsewhere.
2) Gluconeogenic (20-30 days)
Amino acids to glucose. Problem is you need proteins in your body to function- can’t break down too much
3) Ketogenic
Fatty acids to ketone bodies. Get acetyl coA; never build up TCA cycle intermediates for glucose for brain. No glucose, no ketone bodies, brain adapts to using ketone bodies instead of glucose.
4) Terminal
Amino acids used up from remaining protein. Premorbid rise in urea concentration in urine.
Glycogenolytic phase (phase 1)
Only liver exports glucose. Other cells lack glucose 6 phosphatase so they can’t release glucose. This means liver glycogen is rapidly depleted. Liver will break down glycogen and glucose molecules go out for transport. Takes about a day.
Gluconeogenic Phase (phase 2)
Glycogen is gone, but brain still needs lots of energy (still prefers glucose). Fatty acids can’t be used to make glucose, and fatty acids can’t be used by the brain. Only sources of glucose are glycerol from TAG hydrolysis, amino acids from protein***, and odd chain fatty acids. You can form propionyl coA, the precursor for succinyl coA, and increase the concentration of TCA cycle intermediates. Then get the gluconeogenic path. Fatty acids cannot be used easily by brain because they don’t get across the blood barrier very rapidly. There are ways, but they are slow compared with the amount of energy the brain needs
Gluconeogenesis requires 6 ATP, which comes from FA oxidation. You also adapt: gluconeogenic capacity of the liver increases from day 1 to day 7. Most of the enzymes needed for this are needed for DNA.
BIG PROBLEM: Proteins are being degraded too fast. Humans cannot survive loss of 1/3 of their proteins, so would probably last only 20-30 days.
Ketogenic phase (phase 3)
Use energy stored as fat. Ketone body production increases and brain adapts to use ketone bodies. Less glucose is consumed and there is less breakdown of amino acids (20g per day instead of 75g per day). Brain starts to express different enzymes that are more efficient at using ketone bodies than glucose. Liver starts oxidizing FA to acetyl coA, combine to make KB and get increase in blood as a result. Looking at a graph, get a steady value of produced energy from gluconeogenesis and ketoneogenesis.
Terminal Phase (phase 4)
This is the phase where you run out of fat and start degrading massive amounts of protein. Get pre-morbid rise in urea concentration in urine. Then you die
Plasma Glucose Homeostasis: sources of plasma glucose increase and decrease
Increase: diet, gluconeogenesis (liver and kidney- high glucagon promotes this), glycogen (from liver- glucagon stimulates breakdown of glycogen and release of glucose)
Decrease: tissue uptake (muscle and adipose tissue- insulin promotes this), glycogen (liver- insulin stimulates uptake of glucose and synthesis of glycogen in liver), oxidation (CNS, all tissues)
Plasma Glucose Levels
glucose levels get too low, can go into a coma
normal/after a meal is called euglycemia, then get fasting, then hypoglycemia, then coma
Effects of insulin on blood glucose
Uptake of glucose by cells and storage as triacylglycerols and glycogen
High concentration of glucose can modify other proteins and make them non functional. Consequences: damage to peripheral nerves, people in that state could step on a nail and not know, it would get infected. Also causes kidney damage and eventual blindness.
Have to have insulin, if you don’t you et a disease. Concentration of glucose will get too high, leads to neuropathies and nephropathies.
Result of non insulin-dependent diabetes:
Glucose levels always high, WAY higher with disease, can still make some insulin but cells don’t respond to insulin the way they should
(Type 2)
Diabetes mellitus
Lack of insulin function
Urine tastes sweet as glucose is excreted- early diagnostic tool
Major leading cause of death in the US
20% Americans over 60 have diabetes. 5-10% Type 1, others type 2
Diabetes Type 1
Insulin-dependent diabetes mellitus (IDDM)
- lack of pancreatic beta cells, no production of insulin
- cause: autoimmune disease
- treatment: insulin diet (Frequent small meals)
Diabetes Type 2
Non insulin dependent diabetes mellitus (NIDDM)
-body is resistant against insulin
-risk factors: obesity and genetic predisposition
-treatment: change of lifestyle (diet, exercise), insulin
-drugs: to inhibit gluconeogenesis in liver to increase glucose uptake by muscles
symptom is abdominal fat
Consequences of lack of insulin:
1) Impaired glucose uptake by muscle and adipose tissue, leads to high glucose levels in blood
Why are increased glucose levels so damaging?
-cardiovascular problems, cataracts, blindness (remember that glucose has a reactive aldehyde group)
-excretion of glucose by kidneys: dehydration (thirst is diagnostic indication), kidney failure
2) Glucagon prevails (starvation in the presence of high glucose)
-gluconeogenesis active
-high levels of fatty acids and ketone bodies
Cardiovascular problems, ketosis (acetone smell is diagnostic indication). Ketosis can lead to coma, low pH leads to kidney failure as protons are constantly excreted
Diabetic Ketoacidosis
Kbs can be dangerous, they are acidic and can become toxic to a person who is diabetic
Starvation conditions:
-concentration of insulin decreases and glucagon concentration increases
-TAG-> FA’s -> KB’s
-gluconeogenesis becomes more active (where? liver)
-concentration of glucose increases
So far so good…
Normal:
1) more insulin is made
2) insulin activates phosphatase-1 and cAMP phosphodiesterase (degrades cAMP)
3) concentration of cAMP decreases and TAG lipase dephosphorylated
4) less TAG converted to FAs and KBs
Untreated Type 1 diabetic: doesn’t make insulin
1) no insulin made
2) Lots of TAG-> FA’s-> KB’s
3) KB’s accumulate in blood - cause pH to fall
This diabetic condition is known as ketoacidosis
Diabetic ketoacidosis 90mg/100 ml instead of 3
if untreated (insulin infection), the blood pH drops, coma, death
Type 2 Diabetes treatments
GLP-1 modulators: eventide (Byetta), sitagliptin (Januvia)
->targets Glucagon-like peptide-1, dipeptide protease IV
-> enhances insulin secretion by pancreas
Sulfonylureas: Glipizide (glucatrol), glyburide (several brands), glimepiride (Amaryl) -> pancreatic beta cells; K+ channels blocked -> Stimulates insulin secretion by pancreas
(glipizide- small molecule, still have beta cells, insulin being produced but not enough to stimulate muscle and liver cells)
Metformin: suppresses expression of PEPCK and g6p in liver (suppresses gluconeogenesis)
liver cells in low energy state- need to do glycolysis
