Biochemistry: Insulin and Glucagon

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What is the normal range of glucose levels?
70-100mg/dL
Describe the source of glucagon and insulin and what causes the release of each hormone
•Alpha cells produce glucagon in response to low glucose
•Beta cells produce insulin in response to high glucose
1. Most tissues go through glycolysis in order to produce what?
2. Why does the liver go through glycolysis?
1. to generate energy
2. to generate precursors for FA synthesis
What is the main source of carbon for gluconeogenesis?
Amino acids
Effects of glucagon (↑ or ↓?)
1. Glycogenolysis
2. Gluconeogenesis
3. Lipolysis
4. Liver glycolysis
1. Glycogenolysis ↑
2. Gluconeogenesis ↑
3. Lipolysis ↑
4. Liver glycolysis ↓
Effects of insulin (↑ or ↓?)
1. Glycogen synthesis
2. Fatty acid synthesis
3. Triglyceride synthesis
4. Liver glycolysis
1. Glycogen synthesis ↑
2. Fatty acid synthesis ↑
3. Triglyceride synthesis ↑
4. Liver glycolysis ↑
Which of these processes are increased with insulin vs. glucagon?
1. Glycogenolysis
2. Glycogen synthesis
3. Triglyceride synthesis
4. Gluconeogenesis
5. Lipolysis
6. Fatty acid synthesis
7. Liver glycolysis
Insulin increases
1. Glycogen synthesis
2. Fatty acid synthesis
3. Triglyceride synthesis
4. Liver glycolysis

Glucagon increases:
1. Glycogenolysis
2. Gluconeogenesis
3. Lipolysis

What is the effect of glucagon on:
1.Blood Glucose
2. Liver glycogen
3. Adipose triglycerides
4. Muscle Protein
5. Liver glucose metabolism
6. Second messenger system
1.Blood Glucose: ↑ (glucose released to blood)
2. Liver glycogen: Promotes breakdown
3. Adipose triglycerides: Lack of Insulin Promotes TG breakdown and release of FA to blood.
4. Muscle Protein: no effect
5. Liver glucose metabolism: Promotes gluconeogenesis
6. Second messenger system: Heptahelical – Trimeric G
↑ cAMP –> PKA (ser/thr kinase)
What is the effect of insulin on:
1.Blood Glucose
2. Liver glycogen
3. Adipose triglycerides
4. Muscle Protein
5. Liver glucose metabolism
6. Second messenger system
1.Blood Glucose: ↓ (glucose removed from blood)
2. Liver glycogen: Promotes synthesis
3. Adipose triglycerides: Promotes synthesis of TG from liver VLDL TG
4. Muscle Protein: Promotes synthesis of proteins
5. Liver glucose metabolism: Promotes glycolysis (for conversion to fat)
6. Second messenger system: Tyrosine Kinase Receptor (the insulin receptor itself) –> PIP3 –> PKB (ser/thr kinase)
1. What is the major counter-regulatory hormone to insulin?
2. List the other counter-regulatory hormones
1. Glucagon
2. Epinephrine, Norepinephrine, Cortisol
In a high protein meal vs a high carb meal what happens to the levels of insulin and glucagon?
High protein meal: both insulin and glucagon rise
High carb meal: insulin rises, glucagon falls
Consequences of not maintaining glucose and lipid levels.
Excess glucose, lipid and amino acids must be removed from blood.
1. Excess sugar and amino acids would cause a ___________ state.
2. Excess glucose can cause ___________ of proteins
3. Excess lipid can cause _________________
1. Excess sugar and amino acids would cause a hyper-osmotic state.
2. Excess glucose can cause non-enzymatic glycosolation of proteins
3. Excess lipid can cause atherosclerosis
1. Hyperglycemia – high blood glucose
-Can cause hyper-osmotic coma by pulling water out of cells (particularly brain cells)
2. Polyuria – urge to urinate frequently
3. Polydipsia – increased thirst
4. Weight loss – despite good appetite
5. Increased reliance on lipid metabolism
6. Non-enzymatic glycosylation of proteins
-easily detected on hemoglobin
-retinopathy, nephropathy, neuropathy, vascular

Dx?

Diabetes Mellitus
-Autoimmune destruction of β-cells
-Almost undetectable [insulin] in blood

Dx?

Type 1 Diabetes
-Skeletal muscle and liver “resist” action of insulin
-Insulin level can be normal in these patients

Dx?

Type 2 (insulin resistant) Diabetes
-decreased glucokinase activity
-requires ↑ [glucose] to cause ↑ [ATP]
-therefore insulin release only at ↑ [glucose]

Dx?

MODY (maturity onset diabetes of the young)
Glucagon:
1. Both ______ and _______suppress its release
2. _______ and _______increase its release
3. High concentrations of ________ increase glucagon release (even if insulin is also high).
1. Both insulin and glucose suppress its release
2. Epinephrine and cortisol increase its release
3. High concentrations of amino acids (after a high protein meal) increase glucagon release (even if insulin is also high).
-This increases the conversion of excess amino acids to glucose.
Insulin synthesis:
1. Insulin (β-cells) & Glucagon (α-cells) are released into the hepatic portal vein.
2. Pre-pro-insulin is synthesized into the _______ where the short hydrophobic signal sequence is cleaved off the N-terminal, thus yielding pro-insulin.
3. Pro-insulin is sorted in the ______ and packaged into storage vesicles along with ______.
4. Insulin is activated in the vesicles when the _______is cleaved off. The active insulin ppt’s with the Zn++
2. Pre-pro-insulin is synthesized into the rER where the short hydrophobic signal sequence is cleaved off the N-terminal, thus yielding pro-insulin.
3. Pro-insulin is sorted in the Golgi and packaged into storage vesicles along with Zn++.
4. Insulin is activated in the vesicles when the C-peptide is cleaved off. The active insulin ppt’s with the Zn++
Past insulin levels are measured using what?
C-peptide
Release of insulin
1. Elevated glucose causes increased entry into the pancreas cell via the ______ transporter
2. Glucose is trapped in cell by phosphorylation and undergoes glycolysis, CAC and ETC yielding increased ______
3. ATP inhibits _____ channel and induces cell depolarization, and release of vesicles.
1. Elevated glucose causes increased entry into the pancreas cell via the Glut2 transporter (which is a passive and always active transporter).
2. Glucose is trapped in cell by phosphorylation and undergoes glycolysis, CAC and ETC yielding increased [ATP].
3. ATP inhibits K+ channel and induces cell depolarization, and release of vesicles.
Release of insulin
1. When we have high glucose levels it comes in by the _____ transporters –> this will increase _____ inside the cell.
2. ATP shuts down the outward _____ flow keeping. This will help to _______ the cell
3. Once the cell is depolarized; ______ will come in and insulin will be released
4. Which channel is key to the insulin release?
1. When we have high glucose levels it comes in by the Glut2 transporters –> this will increase ATP inside the cell.
2. ATP shuts down the outward K+ flow keeping the positive K+ inside. This will help to depolarize the cell
3. Once the cell is depolarized Ca2+ will come in and insulin will be released
4. The K+ channel is key to the insulin release
How do Sulfonylureas work in the treatment of diabetes?
block K+ channels which helps to depolarize the cell (an lead to insulin release)
Fed State:
Muscle and adipose tissue use which glut transporter?
Glut4
•Promotes storage of glucose as glycogen
•Promotes storage of FAs
•Amino acids are being used to make liver proteins; the other AAs will be used for gluconeogenesis or fatty acid synthesis
•Excess calories go out as FAs –> they are packaged in VLDLs–> broken down by LPL –> and re-packaged in adipose tissue

Fed or fasting state?

Fed state
•Breakdown of fats by sensitization of the adipose to cholinergics
•FFAs are distributed via blood albumin and taken up by the tissues that use them
liver burns FFAs by beta oxidation to generate ATP; the liver burns mostly fat for its energy
•Gluconeogenesis in the liver comes from AAs
•90% of the energy is coming from the burning of fats

Fed or fasting state?

Fasting state
Fasting state:
1. In the fasting state the liver burns FFAs by beta oxidation to generate _____; the liver burns mostly _____ for its energy
2. Gluconeogenesis in the liver comes from what source?
1. In the fasting state the liver burns FFAs by beta oxidation to generate ATP; the liver burns mostly fat for its energy
2. Gluconeogenesis in the liver comes from AAs
insulin promotes ________ synthesis in the muscle
glycogen
Insulin promotes gene expression of enzymes related to insulin’s actions and directly turns on the up-regulation of ______ in muscle and fat & _______ synthesis in liver and muscle
Insulin promotes gene expression of enzymes related to insulin’s actions and directly turns on the up-regulation of Glut4 in muscle and fat & glycogen synthesis in liver and muscle
Insulin ultimately promotes the _____________of our target proteins

Phosphorylation or dephosphorylation?

Insulin ultimately promotes the de-phosphorylation of our target proteins

BOTTOM LINE: insulin will dephosphorylate its target –> this will activate things such as glycogen synthesis

Glucagon promotes the ______________ of our target proteins

Phosphorylation or dephosphorylation?

Glucagon promotes the phosphorylation of our target proteins
Insulin will ↓or ↑?
1. Glycogen breakdown
2. Glycogen synthesis
3. Glycolysis
1. Glycogen breakdown ↓
2. Glycogen synthesis ↑
3. Glycolysis ↑
Glucagon will ↓or ↑?
1. Glycogen breakdown
2. Glycogen synthesis
3. Glycolysis
1. Glycogen breakdown ↑
2. Glycogen synthesis ↓
3. Glycolysis ↓
Beta receptor activation by epinephrine (in the stressed state) or glucagon (in the fasting state) will cause what second messengers to be activated? What will be the overall effect?
•Increase in cAMP –>PKA
•PKA phosphorylates things and allows for the breakdown of glycogen
During the fed state insulin will promote ____________ which will promote the synthesis of glycogen
de-phosphorylation
In the stress state we will also activate the alpha 1 receptors via epinephrine
1. This activates which second messengers?
2. What overall effect will this have?
1. Gαq–>phospholipase C will cleave PIP2–> DAG and IP3
Results in Ca2+ influx via IP3 and PKC activation via DAG
2. PKC–>phosphorylation of the proteins needed for the breakdown of glycogen
1. The liver uses glycolysis to make what?
2. Other tissues use glycolysis to make what?
1. fat
2. energy
1. Insulin promotes what process in the liver?
2. Glucagon promotes what process in the liver?
1. glycolysis
2. gluconeogenesis
Insulin will activate what three steps of glycolysis?
Step 1: glucokinase
Step 3: PFK-1 (phosphofructokinase)
Step 10: pyruvate kinase
1. Insulin turns on the fat synthesis by doing what to the rate controlling enzyme?
2. Glucagon will do the opposite and will ___________ the rate controlling enzyme in fat synthesis, to turn it off
1. Insulin turns on the fat synthesis by dephosphorylating the rate controlling enzyme
2. Glucagon will do the opposite and will phosphorylate the rate controlling enzyme in fat synthesis, to turn it off
What is the rate controlling step in fatty acid synthesis?
Acetyl CoA carboxylase (a biotin dependent enzyme)
Categories: Biochemistry