What are the two amino acid chains in insulin called?
A = alpha chain (Acid chain)
B = Beta
_____is the most important anabolic hormone
True or False. The M&M associated with diabetes is due to problems with carb metabolism from lack of insulin.
FALSE! Really the problems w/fat and protein metabolism that lead to the pathophysiology changes we’re familiar w/ that are seen in the diabetic patient that lead to the morbidity and mortality.
The primary target organ for insulin is ______ ______ (where we store a lot of our glycogen)
What is the 1/2 life of insulin
Insulin will increase the rate of glucose transport into the resting muscle cell by ___x.
normal adult will secrete ~__units of insulin/day
Is most of the insulin bound to protein?
NO! Most of the insulin will be unbound to protein (peptide hormone so not highly protein bound)
Within seconds of binding to the receptor the membranes of ~___% of body cells will markedly increase the amount of glucose they’re able to take up
Do the neurons in the brain take up glucose and store it?
NO, brain is dependent on dextrose as an energy source.
What happens after glucose is taken up by the muscle and fat cells?
After glucose is taken up it gets phosphorylated, and becomes a substrate for all of those metabolic reactions.
Besides glucose uptake, what else happens when insulin binds to the receptor?
The membrane becomes more permeable to many AA and ions (K+ and phosphate) and those will move into the cell as well.
Give insulin (and D50W) to treat hyperkalemia. To move K+ extracellular fluid to intracellular fluid
TRUE or FALSE. Resting muscle membrane only slightly permeable to glucose in absence of insulin
Large amount of insulin secreted after meals, rapid transport of glucose and preferential use of glucose by those muscle fibers so the increase rate of glucose transport goes up by 15x.
After glucose gets absorbed it’s stored as liver & muscle as glycogen. What happens between meals?
Blood glucose drops in between meals so the glycogen gets split back into glucose and released into the blood
Can exercise change the permeability of the membrane to glucose?
YES! With moderate to heavy exercise causes contraction of the muscle which makes those fibers more permeable to the glucose.
Describe what happens following glucose injestion
Insulin secreted inactivates liver phophorylase
Insulin enhances glucose uptake from blood → liver by ↑ glucokinase activity
Insulin increases activity of enzymes leading to glycogen synthesis
Insulin secreted inactivates liver phophorylase. How does this help control blood glucose after a meal?
Phophorylase: will cause liver glycogen to split into glucose (don’t want splitting after a meal because glucose level is high enough)
What is Glucokinase?
the enzyme that converts glucose to glucose-6-phosphate and the 1st step of glycolysis.
The phosphorylate (The glucose-6-phosphate) form can’t diffuse through the cell membrane, temporarily trapped in the liver cell (like ion trapping)
This is how insulin enhances glucose uptake from the blood into the liver. By increasing the activity of glucokinase
The net result on insulin effects of CHO metabolism following a meal is....
glycogen can ↑ to a total of 5-6% of liver mass or 100 gm of stored glycogen
glycogen can ↑ to a total of ___% of liver mass or 100 gm of stored glycogen
What happens with a decrease in blood glucose?
↓ insulin secretion by beta cells
Glycogen synthesis stops
Glycogen is split (lysed) into glucose with activation of phosphorylase
Glucose phosphatase now activated by lack of insulin removing the phosphate radical from glucose
Glucose diffuses back into the blood
Glucose that enters the liver cells is 1st used for local hepatocyte metabolism. Liver is active organ and needs certain amount of nutrition itself, used to support those metabolic pathways. Any excess will get stored as glycogen. But then beyond that, what happens if there is still excess glucose?
will be converted to fatty acids.
These then get packaged as triglycerides and very low density glycoproteins and stored as fat.
Besides conversion to fatty acids, what else happens if there is an excess of glucose?
An inhibition of gluconeogenesis (synthesis of glucose from non carbohydrate sources)
Another example of le chatelier's principle. There will be a decrease and amount of activity needed for other enzymes needed for gluconeogenesis.
Does the brain need insulin for glucose uptake?
No! Insulin isn’t necessary for glucose uptake & utilization. Brain cells are permeable to glucose
Why is glucose so important for the brain?
Glucose is the only substrate used for energy
If glucose drops below levels of __ mg/100ml CNS symptoms develop
50; the patient will develop CNS symptoms, irritability, seizures, coma, somewhat on a continuum
What effect does insulin have on fat metabolism?
Insulin promotes fat synthesis & storage
Because as insulin increases glucose utilization we don’t need to use fat as an energy source so fat gets stored
Describe the process of how excess glucose can be stored as fat
Besides storing excess glucose as fat, how else does insulin promote the storage of fat?
Insulin will inhibit enzyme Lipase (break down fat) so inhibit that then insulin promotes the storage of fat
TRUE or FALSE. Insulin promotes glucose transport via cell membrane into fat cells
TRUE. Some of that glucose will become fatty acids, some paired of w/glycerol to form triglycerides which is ultimately the storage form of fat.
What happens to fat metabolism if we don't have enough insulin?
We can't store it so we use it for energy
Lipolysis of stored fat (triglycerides) & release of fatty acids & glycerol
↑ cholesterol & phospholipid concentrations
Ketosis & acidosis
Where can fatty acids be used for energy?
FA can be used for energy for all tissues w/the exception of the brain
How does insulin deficiency effect fat metabolism so there is acidosis and ketosis?
A lack of insulin will cause an excess amount of acetoacetic acid (ketone bodies) to be formed in liver.
As fatty acids get oxidized, (in the mitochondria) there will be excess of that acetyl-CoA.
Without insulin that gets converted to acetoacetic acid. Also some of the acetoacetic acid gets converted to beta-hydroxybutyric acid and then finally to acetone.
The three ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone) are responsible for acidosis and ketosis
What effect does insulin have on protein metabolism?
Protein synthesis & storage
Inhibits protein breakdown
(Insulin will simulate the transport of many AA into the cell)
What effect does LACK of insulin have on protein storage?
Protein depletion & increased amino acids → blood
Catabolism of protein → ↑ urea excretion
The basal rate of insulin secretions is __unit/hr. This can increase ___fold after ingestion of food,
increase 5-10 fold
1/2 life of insulin in circulation is about 5min but the clinical duration may be longer. Why?
because of delays in binding and release from the receptors.
What happens is there is a high level of insulin all receptor are saturated, not more potent effect (ceiling effect) but the duration can last longer.
The release of insulin is primarily due to the blood glucose level. What else can effect insulin secretion?
Also the result of response to AA along w/other hormones of GI tract because of the ingestion of gluten.
The ANS has an effect, PNS vagal stimulation will cause insulin release and so does beta adrenergic SNS stimulation
Other nutrients like AA will stimulate insulin release from the beta cells.
Sulfonylureas will stimulate insulin secretion and may also increase the tissue response to insulin
Why is the patient who has liver or renal disease more at risk for hypoglycemia?
Insulin is metabolized by the liver and eliminated by the kidney. In patient that have hepatic dysfunction or renal failure there can be a prolonged effect of insulin and at risk for hypoglycemia
What can increase insulin secretion? (Name all the factors Sue listed on that slide)
↑Blood free fatty acids
↑Blood amino acids
GI hormones (gastrin, cholecytokinin, secretin, gastric inhibitory peptide)
Glucagon, growth hormone, cortisol
PNS stimultion (Ach)
β adrenergic stimulation
Insulin resistance (obesity)
Sulfonylurea drugs (glyburide, tolbutamide)
What can decrease insulin secretion?
α adrenergic activity
Normal fasting glucose level is in range of mg/dL. At that rate the insulin secretion is minimal, __nanograms/min/kg
What happens if we give a patient a glucose challenge?
The insulin levels will increase in 2 stages. Initial 10fold increase, within 3-5minutes. And this is because of the dumping of the pre-formed insulin from the beta cells.
And in another 5-10min, that high rate of insulin will decrease about ½ down towards the normal baseline.
Then about 15min later, after that challenge the insulin secretion will again increase reaching a new plateau in about 2-3hrs. That’s from not only the release of more pre-formed insulin but the synthesis and release of new formed insulin from the cells
There is a feedback control. When blood glucose level is above ___mg/dL (just above normal range) the insulin secretion rate will increase rapidly that is ___-___x the basal level
Carbs vs Fats metabolism. How does insulin effect them
Insulin promotes utilization of CHO & depresses utilization of fats so…..↓ Insulin causes fat utilization except by the brain
What primarily controls the switch from CHO to Fat metabolism?
Besides blood glucose, what other factors are involved in the switch from CHO to fat metobolism?
Growth hormone (ant. pituitary)
Cortisol (adrenal cortex)
Epinephrine (adrenal medulla)
Glucagon (alpha cells of the pancreas)
GH & Cortisol will inhibit glucose utilization and promote fat utilization.
Epi causes glycogenolysis (increased level of glucose) and will also cause lipolysis (increased levels of fatty acids)
Epi essentially increases both glucose and fatty acid utilization
What is glucagon and where does it come from?
Comes from the alpha cells of the islets of Langerhans
Compared to insulin, what is the effect of glucagon? What is its target organ?
Effect of glucagon is antagonistic to that of insulin.
Target organ is liver again
What is the release of glucagon stimulated by?
Release is stimulated by hypoglycemia and inhibited by hyperglycemia.
Blood glucose concentration is important! Regulation of glucagon release is not well understood. Release is also stimulated by high levels of AA and by epinephrine (Beta 2 mechanism).
How does epi effect insulin and glucagon?
Catecholamines in general will cause a decrease in insulin and increase in glucagon both of which cause an increase in blood sugar.
What is the physiological effect of glucagaon?
Increase plasma levels of glucose.
Causes both glycogenolysis and also gluconeogensis
Besides causing both glycogenolysis and also gluconeogensis, what else can glucagon do in HIGH concentrations? (these effects are minimal in the normal individual)
Enhance the strength of the heart
Increase blood flow to some tissues, especially the kidneys.
Enhance bile secretion.
Inhibit gastric acid secretion.
Somatostatin is a polypeptide with __ amino acids
What is somatostatin secreted by?
Secreted by delta cells
Is the half life of Somatostatin long or short?
Very short half-life = 3minutes
What is the principle role of somatostatin?
Principle role: to increase length of time food in GI tract to prevent the rapid exhaustion of food nutrients
Secretion of somatostatin is stimulated by...(4 things)
Increased blood glucose
Increased amino acids
Increased fatty acids
Increased GI hormones
The liver acts as a buffer for glucose control. When blood sugar level increases after a meal, insulin levels will also increase. As much as ___ of the glucose absorbed from GI tract gets stored in the liver as glycogen
2/3. In between meals when glucose level falls the glycogen will split and get released back as glucose. This will reduce BS fluctuations that would occur otherwise to about 1/3 of what it would be
In severe hypoglycemia the hypothalamus is stimulated by .........
the SNS such that epinephrine from the adrenal medulla causes additional glucose to be released from the liver
Over a period of hours to days, GH & cortisol are secreted due to hypoglycemia & this does what?
decreases the rate of glucose utilization by most cells of the body shifting to fat utilization
Normally insulin feedback is more important than the glucagon except
Glucose is the only nutrient normally used by the
brain, the retina, and the germinal epithelium of the gonads
TRUE or FALSE. Glucose exerts a high osmotic pressure in the ECF which could cause cellular dehydration
TRUE. Severe hyperglycemia causes glycosuria and an osmotic diuresis
High level of glucose, high osmotic pressure in ECF then water being drawn by osmosis from the cell into the ECF to try and normalize that.