7.4. Insulin secretion and the regulation of the secretion. The effects of insulin on the intermediary metabolism. Diabetes mellitus. Flashcards
1
Q
I. Basics
1. What is Intermediary metabolism?
A
- Metabolic steps within the cells in which the nutrient molecules or foodstuffs are metabolized and converted into cellular components and/or provide energy => it provides the appropriate energy supply for the cells and tissues.
- Energy donors: carbohydrates, fats/lipids, AAs
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Q
I. Basics
2. What are the energy donors of intermediary metabolism
A
carbohydrates, fats/lipids, AAs
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Q
I. Basics
3. Is the site of storage extracellular or intracellular?
A
INTRACELLUAR!!!
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Q
I. Basics
4. Describe the intracellular storage of amino acids
A
- Can be glycogenetic
- But too “valuable” because of other functions of proteins
- During breakdown, NH3 or urea is produced
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Q
I. Basics
5. Describe the intracellular storage of lipids
A
- Ideal storage property
- Only oxidative breakdown
- Not suitable for every tissue
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Q
I. Basics
6. Describe the intracellular storage of carbohydrate
A
- Appropriate for every tissue
- Bad storage properties
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Q
I. Basics
7A. What are the 3 Major players ‘’effectors’’ of the intermediary metabolism
A
The regulation depends on hormones produced by different endocrine organs
1. Liver: ‘’the center’’
2. Adipose tissue:
3. Skeletal muscle
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Q
I. Basics
7B. One of Major players ‘’effectors’’ of the intermediary metabolism is
“LIVER”
=> Explain
A
Liver: ‘’the center’’
- Gluconeogenesis can direct sources to provide glucose
(The regulation depends on hormones produced by different endocrine organs)
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Q
I. Basics
7C. One of Major players ‘’effectors’’ of the intermediary metabolism is
“ADIPOSE TISSUE”
=> Explain
A
- White adipose tissue: storage site of fat/lipids
- Actually the largest endocrine tissue => produces regulatory molecules
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Q
I. Basics
7D. One of Major players ‘’effectors’’ of the intermediary metabolism is
“SKELETAL MUSCLE”
=> Explain
A
- Largest energy consumer if we exercise
- Other energy consumers: Brain, CT, bone tissue, skin, kidney etc.
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Q
I. Basics
8. Depending of the demand
=> What are the processes that lead to elimination of transport nutrients?
A
- Protein synthesis
- Lipogenesis
- Glycogenesis
- Glycolysis
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Q
I. Basics
9. Depending of the demand
=> What are the processes that lead to production of transport nutrients?
A
- Proteolysis
- Lipolysis
- Glycogenolysis
- Gluconeogensis
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Q
I. Basics
10A. What are the 3 basic rules of the regulation of intermediary metabolism?
A
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Q
I. Basics - basic rules of the regulation
10B. How do we keep the plasma [glucose] at the normal level?
A
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Q
I. Basics - basic rules of the regulation
10C. What is the major regulator?
A
Insulin
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Q
I. Basics
11. Make a schematic diagram of regulation in intermediary metabolism?
A
17
Q
II. Insulin synthesis and secretion
1. How is insulin secreted?
A
Insulin is secreted by β-cells in the endocrine regions of the pancreas: the islets of Langerhans.
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Q
II. Insulin synthesis and secretion
2A. How does synthesis of insulin occur?
A
19
Q
II. Insulin synthesis and secretion
2B. How is pro-insulin processed?
A
- Pro-insulin is sent to the ER and folded properly, the connecting peptide (C-peptide) is cleaved, and the mature insulin + C-peptide are packaged in equal amounts in secretory granules (Golgi)
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Q
II. Insulin synthesis and secretion
3. What are the values of secretion of insulin during fasting, mixed feeding? Also the insulin content of pancreas
A
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Q
II. Insulin synthesis and secretion
4A. Insulin is secreted by β-cells due to a variety of factors
=> What are these factors?
A
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Q
II. Insulin synthesis and secretion
4B. What are the features of incretins?
A
- Incretins (GLP + GIP): hormones that stimulate a decrease in blood glucose levels
+) Released due to orally ingested glucose, regulates insulin release by feed- forward mechanism
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Q
II. Insulin synthesis and secretion
5. How does glucose affect the cell?
A
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Q
II. Insulin synthesis and secretion
6. What is the mechanism of ↑[glucose] that leads to ↑insulin secretion
A
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II. Insulin synthesis and secretion - Pharmacological regulation of the inwardly rectifying KATP-channel
7. What should we do if the production of insulin on the β-cells is insufficient?
When the production of insulin on the β-cells is insufficient
-> diabetes (↑[glucose]).
=> Since the KATP-channels has sulphanylurea (SU)-receptors, we can use sulphanylurea to bind and close the channel
-> depolarization
-> insulin secretion
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II. Insulin synthesis and secretion - Pharmacological regulation of the inwardly rectifying KATP-channel
8. What should we do if there is an overactivation of β-cells?
If there is an overactivation of β-cells, we can use diazoxide.
- It allows KATP to remain opened even when ATP is present, thereby hyperpolarizing the cell => inhibits insulin secretion
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II. Insulin synthesis and secretion - β-cell mechanism
9A. Describe β-cell mechanism
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II. Insulin synthesis and secretion - β-cell mechanism
9B. Describe β-cell mechanism When the cell is well supplied with energy donors?
When the cell is well supplied with energy donors:
- AMP
-> ADP -> ATP
=> insulin secretion
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II. Insulin synthesis and secretion - β-cell mechanism
9C. Describe β-cell mechanism When energy donors are sufficient?
- When energy donors are sufficient ↑[AMP] (no ATP produced) AMP will also regulate AMP-kinase, which inhibits the insulin synthesis = NO INSULIN SECRETION
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II. Insulin synthesis and secretion - β-cell mechanism
9D. Describe β-cell mechanism When glucose enters the cell?
- When glucose enters the cell, AMP -> ATP and ↓[AMP] = no AMP-kinase produced
=> insulin synthesis starts (with help of Ca2+-calmodulin)
=> insulin secretion
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II. Insulin synthesis and secretion - Components of the β-cell regulation
10A. What are the activators in β-cell regulation?
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II. Insulin synthesis and secretion - Components of the β-cell regulation
10B. What are the AAs that act as activators of β-cell regulation?
lysine, arginine, leucine
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II. Insulin synthesis and secretion - Components of the β-cell regulation
10C. What is the role of incretins as activators of β-cell regulation?
Incretins: GIP (glucose-dependent insulinotropic peptide) and GLP (glucagon-like peptide) are released due to orally ingested glucose and have stimulatory effect on
insulin
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II. Insulin synthesis and secretion - Components of the β-cell regulation
10D. What is the role of Glucagon as activators of β-cell regulation?
Glucagon: induces insulin by activating a Gq-protein that causes ↑[Ca2+] and thus insulin release
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II. Insulin synthesis and secretion - Components of the β-cell regulation
10E. What is the role of Vagus as activators of β-cell regulation?
ACh -> (Gq)M1-receptor -> PLC -> IP3 -> ↑[Ca2+]
=>↑[cAMP] is the 2nd messenger for most of them
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II. Insulin synthesis and secretion - Components of the β-cell regulation
11A. What are the inhibitors of β-cell regulation?
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II. Insulin synthesis and secretion - Components of the β-cell regulation
11B. What happen if there is an Acute exposure of the pancreatic β-cell to FFA?
Acute exposure of the pancreatic β-cell to FFA results in an increase of insulin release.
=> BUT a chronic exposure results in desensitization and suppression of insulin secretion
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II. Insulin synthesis and secretion - Components of the β-cell regulation
12. Make the schematic diagram for the β-cell regulation?
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II. Insulin synthesis and secretion
13. What is the structure of Insulin receptor?
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II. Insulin synthesis and secretion
14. What is the mechanism of Insulin receptor?
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II. Insulin synthesis and secretion
15. What are the steps of GLUT4 transposition?
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II. Insulin synthesis and secretion
16. How does Exercise-responsive GLUT4-containing vesicle work?
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II. Insulin synthesis and secretion
17. Glucose transport into the cells increases, wherever GLUT4 transporters are present:
=> T/F??
TRUE!!!!
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II. Insulin synthesis and secretion
18. What are the features of Insulin-dependent glucose uptake?
Insulin-dependent glucose uptake: (GLUT4)
- Pancreas α-cell, CT, lymphoid tissue
- Adipose tissue and skeletal muscle (they also have GLUT1 present – allows only smaller glucose transport)
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II. Insulin synthesis and secretion
19. What are the features of Insulin-independent glucose uptake?
- GLUT2: liver, kidney, intestine
- GLUT3: brain, RBC, cornea
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III. ACTION OF INSULIN
1. What are the features of insulin?
- Insulin a strongly anabolic hormone, and it is often taken by bodybuilders to help them gain more muscles.
- Insulin promotes the uptake of AAs (proteins) into the cells contributing to its anabolic effect (muscles bruv!!)
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III. ACTION OF INSULIN
2. What are the 4 general insulin effects?
General insulin effects: (exerted in all the tissues)
1. Amino acid transport into the cells↑
=> protein synthesis↑
2. K+-transport into the cells↑ (activation of Na+/K+-ATPase)
3. Activation of phosphodiesterase
=> ↓[cAMP]
4. Growth promoting effect
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III. ACTION OF INSULIN
3A. The role of liver when it comes to insulin?
- Liver is both a target organ for insulin action and a major site of insulin degradation.
- Glucose enters the hepatocytes through GLUT2 transporters (insulin-independent).
- Blood [insulin] in portal vein is 3-4 times greater than its concentration in the systemic circulation.
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III. ACTION OF INSULIN
3B. What are the 3 effects of insulin on the liver?
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III. ACTION OF INSULIN
4A. What are the effects of insulin in the adipose tissue?
Insulin-regulated GLUT4 translocation: insulin induces translocation of GLUT4 to PM via the PI3-kinase pathway
1) Insulin promotes lipogenesis (formation of triglycerides)
2) Also increased FFA synthesis from glucose
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III. ACTION OF INSULIN
5. What are the Effects of insulin on the skeletal muscle?
Glucose enters the muscle through GLUT4 (insulin- dependent). Insulin-regulated GLUT4 translocation induces translocation of GLUT4 to PM via PI3-kinase pathway
1) Insulin stimulates glycolysis and glycogenesis
2) Protein synthesis↑ & proteolysis↓
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III. ACTION OF INSULIN
6. Make a table to demonstrate the effects of insulin
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IV. DIABETES MELLTIUS
1. What are the features of Diabetes mellitus type 1 (1TDM)
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IV. DIABETES MELLTIUS
2. What are Abnormal metabolic processes in 1TDM?
Impaired β-cell function (insulin secretion↓)
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IV. DIABETES MELLTIUS
3. What are the effects of diabetes mellitus on Muscle?
- Glycogen storage↓, because they do not absorb glucose due to the absence of GLUT4 on PM
- Protein breakdown -> lactate -> gluconeogenesis in liver (↑blood sugar even
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IV. DIABETES MELLTIUS
4. What are the effects of diabetes mellitus on adipose tissue?
- Never get the insulin signal to stop lipolysis: so they release glycerol
(-> gluconeogenesis) + FFA ( -> ketogenesis) -> liver (↑glucose)
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IV. DIABETES MELLTIUS
4. What are the effects of diabetes mellitus on Pancreatic α-cells?
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IV. DIABETES MELLTIUS
5. Which hormone will we add during DM? Why?
Somatostatin added during DM, will reduce the liver-consequences of insulin deficiency:
- Insulin is still deficient, but
glucagon will be inhibited (only target α-cell)
- Only use somatostatin in tumors in this case
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IV. DIABETES MELLTIUS
6A. What are the 2 main Consequences of the metabolic disturbance?
1. Hyperglycemia
2. Ketonemia (acetoacetic acid, β-OH-butyric acid)
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IV. DIABETES MELLTIUS
6B1. One of Consequences of the metabolic disturbance is
"Hyperglycemia"
=> Explain
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IV. DIABETES MELLTIUS
6B2. One of Consequences of the metabolic disturbance is
"Hyperglycemia"
=> What is Osmotic diuresis?
water and electrolyte loss (Na+, Cl-)
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IV. DIABETES MELLTIUS
6C. One of Consequences of the metabolic disturbance is
"Ketonemia"
Ketonemia (acetoacetic acid, β-OH-butyric acid):
- Without insulin, the body is basically in starvation mode despite being extremely hyperglycemic.
- Ketone bodies are produced in the liver and released into the blood
=> diabetic ketoacidosis and all the problems associated with metabolic acidosis (hyperventilation + vomiting => H2O-loss + diabetic coma)
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IV. DIABETES MELLTIUS - Diagnosis of DM
7. What are the 3 tests for Diagnosis of DM?
1. Glucose tolerance test
2. Glycated hemoglobin (HbA1c)
3. C-peptide
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IV. DIABETES MELLTIUS - Diagnosis of DM
8A. How do we take Glucose tolerance test?
Start out by fasting and then ingest a large amount of glucose, then test blood sugar every 30 minutes for 2 hours and see how it responds (old treatment method)
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IV. DIABETES MELLTIUS - Diagnosis of DM
8B. What are the 2 main measurements of Glucose tolerance test?
- IFG = impaired fasting glucose
- IGT = impaired glucose tolerance
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IV. DIABETES MELLTIUS - Diagnosis of DM
8C. What does IFG = impaired fasting glucose indicate in Glucose tolerance test?
- Before the meal
- Less than 6,1mM = normal, above 7,0mM = diabetic, in range of 6,1-7,0mM = IFG => glucose higher than it should be, but still not diabetic
- If someone has IFG => glucose tolerance test
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IV. DIABETES MELLTIUS - Diagnosis of DM
8D. What does IGT = impaired glucose tolerance indicate in Glucose tolerance test?
- Measured in the end
- If concentration below 7,8mM = tolerance normal, if above 11,1mM = diabetic (exogenous hyperglycemia)
- Between 7,8-11,1mM = IGT
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IV. DIABETES MELLTIUS - Diagnosis of DM
9. How does Glycated hemoglobin (HbA1c) test work?
- This is used to get a longer-term idea of the average blood sugar level.
- In presence of continuously high blood glucose concentration, Hb tends to bond with some of the glucose and thus become ‘’glycated’’.
- People with diabetes will have abnormally high levels of glycated hemoglobin.
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IV. DIABETES MELLTIUS - Diagnosis of DM
10. How does C-peptide test work?
C-peptide: a peptide fragment from insulin synthesis that can be detected in the urine and corresponds to the insulin secretion
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IV. DIABETES MELLTIUS
11. What are the features of Diabetes mellitus type II?
Diabetes mellitus type II: (non-insulin dependent, adult diabetes, insulin resistance)
- This is associated with lifestyle and the damaging effects of eating a diet that pushes the limits of the ability for the pancreatic β-cells to produce insulin.
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IV. DIABETES MELLTIUS
12. Diabetes mellitus type II is associated with lifestyle and the damaging effects of eating a diet that pushes the limits of the ability for the pancreatic β-cells to produce insulin.
=> Explain
- Strong correlation with central obesity (abdominal fat) and lack of exercise.
- DM type II often accompanies ‘’metabolic syndrome’’ – the 3 other major syndromes related to lifestyle: atherosclerosis, hypertension and coronary artery disease
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IV. DIABETES MELLTIUS
13. DM type II often accompanies ‘’metabolic syndrome’
=> What does it mean?
DM type II often accompanies ‘’metabolic syndrome’’ – the 3 other major syndromes related to lifestyle: atherosclerosis, hypertension and coronary artery disease
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IV. DIABETES MELLTIUS
14. What does a person with DM type II need?
A person with DM type II may need twice as much insulin necessary to maintain or keep glucose levels normal
=> so there is an impaired response to insulin and resistance from tissues that normally take it up
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IV. DIABETES MELLTIUS
15. What happen to Serine-phosphorylation of the insulin receptor substrate (IRS) if there is insulin resistance?
- IRS-1 together with tyrosine kinase phosphorylates on several occasions (normal response)
- But when substances (insulin, triglycerides, TNFalpha, resistin, IL6) are present, they cause serine-phosphorylation -> IRS = insulin resistance (signaling does not work)
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IV. DIABETES MELLTIUS
16. Make a schematic diagram for insulin resistance in DM type II
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IV. DIABETES MELLTIUS
17. What is The role of the adipose tissue in the energy metabolism?
1.Triglyceride storage
2. Production of regulating peptide mediators: adipocytokines => adipocytokine production reflects the triglyceride content of the adipocytes (the nutritional state)
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IV. DIABETES MELLITUS
18. What is the role of adiponectin?
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IV. DIABETES MELLITUS
19. Why does the central form (visceral) obesity have particular significance in the development of insulin resistance and NIDDM?
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IV. DIABETES MELLITUS
20. What is the role of 11Beta-hydroxysteroid dehydrogenase-1?
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IV. DIABETES MELLITUS
21. Make a schematic diagram for transcriptional regulation of adipocyte derived mediators
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IV. DIABETES MELLITUS
22A. What are the 3 treatments for T2DM?
1. Diet
2. Exercise
3. Medications
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IV. DIABETES MELLITUS
22B. How should you treat T2DM with diet?
- Reduces the lipid content of adipose tissue
- Increases adiponectin secretion (in other insulin target tissues: triglyceride↓,
(insulin resistance↓), resistin, TNFalpha and IL6 secretion↓)
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IV. DIABETES MELLITUS
22C. How should you treat T2DM with exercise?
- GLUT4 translocation to the PM
- Muscle glucose consumption↑
- Blood plasma [glucose] ↓
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IV. DIABETES MELLITUS
22D1. How should you treat T2DM with MEDICATIONS?
Use
1. Sulfanylurea
2. GLP
3. TZD
4. Biguanidines
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IV. DIABETES MELLITUS - medications
22D2. What is the mechanism of Sulfanylurea in treatment for T2DM?
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IV. DIABETES MELLITUS - medications
22D3. What is the mechanism of GLP in treatment for T2DM?
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IV. DIABETES MELLITUS - medications
22D4. What is the mechanism of TZD in treatment for T2DM?
