Cellular effects of metformin, a drug for diabetes mellitus
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- Cellular effects of metformin, a drug for diabetes mellitus
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Cellular effects of metformin, a drug for diabetes mellitus
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[post_date] => 2024-12-23 10:38:14
[post_date_gmt] => 2024-12-23 15:38:14
[post_content] => Practice Passage (Question 1-5)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Type II diabetes mellitus is caused by a relative lack of or resistance to the protein insulin, which functions in maintaining normal blood sugar levels by facilitating transport of glucose into cells. Metformin is a common, effective medication for Type II diabetes mellitus. The drug has been shown to reduce rates of gluconeogenesis and increase uptake of glucose from the blood by skeletal muscles, but its specific mechanism of action is unknown.
Researchers investigating metformin’s mechanism of action isolated hepatocytes from rats. They suspected metformin may interact with AMPK, a protein involved with a wide range of metabolic effects, such as increasing hepatic fatty acid oxidation, reducing hepatic glucose production (HGP), and reducing insulin secretion by beta cells of the pancreas. The researchers examined the activity of AMPK in hepatocytes treated with metformin, AMP (an endogenous allosteric activator of AMPK), or a control solution. The cells treated with metformin were found to have increased AMPK activity compared to the control solution (Figure 1a). The researchers performed a similar experiment in vitro with purified AMPK and its downstream substrate and found that metformin had no effect on AMPK activity (Figure 1b).
Figure 1: The effect of metformin on AMPK activity was measured in hepatocytes (a) and in vitro (b). Hepatocytes were incubated for one hour with a buffered solution (negative control), AMP (positive control), or a specified concentration of metformin. White: control solution; gray: AMP; black: metformin. *P < 0.05, **P < 0.01
The researchers also discovered an inhibitor called Compound K that directly interacts with AMPK. Adding the inhibitor to hepatocytes incubated with metformin showed that Compound K attenuates metformin’s ability to reduce HGP (Figure 2).
Figure 2: Compound K inhibits metformin’s usual effect of reducing HGP. Open squares: control; filled diamonds: metformin; filled circles: metformin and Compound K. *P < 0.05, **P < 0.01
Adapted from: Zhou et al. "Role of AMP-activated Protein Kinase in Mechanism of Metformin Action." Journal of Clinical Investigation 108.8 (2001): 1167-174. Web.
[post_title] => Cellular effects of metformin, a drug for diabetes mellitus
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[question] => Which statement about Compound K is most likely to be true?
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[answer] => 3
[description] => Reason for Correct Answer:
The passage, including the plot in Figure 2, does not tell us much about the biochemical properties of the inhibitor, Compound K.
Compound K lessens the activating effects of metformin on AMPK.
Activated AMPK decreases hepatic glucose production. If metformin is less capable of activating AMPK, blood glucose levels will rise.
Higher blood glucose levels will trigger greater release of insulin from the pancreas. It is most likely true that Compound K will increase blood insulin levels in a diabetic patient taking metformin.
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[answers] => Array
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[each_answer] => A. Compound K may cause hypoglycemia in a diabetic patient taking metformin.
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[each_answer] => B. Compound K decreases the rate at which AMPK binds substrate and is therefore a non-competitive inhibitor.
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[each_answer] => C. Compound K increases blood insulin levels in a diabetic patient taking metformin.
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[each_answer] => D. Compound K lowers the Vₘₐₓ of AMPK and is therefore a non-competitive inhibitor.
)
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => For which reason did the researchers most likely choose hepatocytes as a target for metformin treatment?
[value] => Array
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[answer] => 4
[description] => Reason for Correct Answer:
The passage states that metformin “increases the uptake of glucose by skeletal muscles.” Therefore its effects are not isolated to the liver.
Insulin secretion occurs in beta cells, which are located in the pancreas.
The main focus of the researchers’ investigation is the effect of metformin on hepatic glucose production via the protein AMPK.
The researchers most likely chose to target hepatocytes because hepatocytes increase blood glucose levels through gluconeogenesis. They wanted to investigate the effects metformin on gluconeogenesis
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[0] => Array
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[each_answer] => A. To investigate the effects of metformin on insulin secretion
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[1] => Array
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[each_answer] => B. The hepatocytes that were removed will regenerate in the livers of the rats.
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[each_answer] => C. The effects of metformin are isolated to the liver.
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[each_answer] => D. To investigate the effects of metformin on gluconeogenesis
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Which of the following would be likely to increase blood glucose levels of a diabetic patient?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Insulin’s main function is to facilitate transport of glucose into cells, thus reducing blood glucose levels.
The protein AMPK decreases hepatic glucose production. Therefore, a molecule that activates AMPK will decrease blood glucose levels.
AMP and Metformin both activate AMPK, while Compound K is a direct inhibitor of AMPK. Therefore, Compound K is likely to increase blood glucose levels of a diabetic patient.
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[answers] => Array
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[0] => Array
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[each_answer] => A. AMP
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[each_answer] => B. Compound K
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[each_answer] => C. Metformin
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[each_answer] => D. Insulin
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[quiz_unique_key] => 1403770772
[question] => Which of the following are possible explanations for why metformin increases AMPK activity in hepatocytes, but not in vitro?
I: Metformin acts on a protein upstream of AMPK
II: An inhibitor of AMPK is present in the in vitro experiment
III: Metformin changes the sensitivity of AMPK to phosphorylation
IV: Metformin changes the sensitivity of AMPK to phosphatases
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
The fact that metformin affects AMPK within cells, but not outside of cells in vitro tells us that metformin does not have a direct activating effect on AMPK. Metformin must require the presence of some other protein or compound to activate AMPK.
It is unlikely that an inhibitor of AMPK is present because the AMPK is purified.
Phosphorylation often activates or deactivates an enzyme. Metformin could interact with AMPK to make it more sensitive to phosphorylation by another protein that is not present in vitro.
Metformin could activate a protein upstream of AMPK, which would go on to activate AMPK. An upstream protein would not be present in vitro.
A phosphatase enzyme removes a phosphate group from its substrate, often causing deactivation of another protein. The addition of metformin may make AMPK a worse substrate for such an enzyme, but this same effect would not be observed in vitro.
xplanations I, III, and IV are all possible explanations for why metformin affects AMPK activity in cells but not in vitro.
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[each_answer] => A. I, II, III, and IV
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[each_answer] => B. I, III, and IV
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[each_answer] => C. III and IV
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[each_answer] => D. I only
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[quiz_unique_key] => 1403770772
[question] => How would starving the rats for 24 hours prior to experimentation affect the activity of the extracted hepatocytes?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
Starvation takes away the rats’ main source of glucose (food), which causes them to produce glucose by other methods.
Glycolysis is the breakdown of glucose to pyruvate to produce ATP. This rate would decrease during starvation to prevent unnecessary use of glucose.
Gluconeogenesis is the reverse of glycolysis. This rate would increase during starvation to produce more glucose.
Lipolysis is the breakdown of fats. The rate of lipolysis increases during starvation as a means of producing glucose.
Glycogenolysis is the breakdown of the glycogen to polymer to individual units of glucose. During starvation, the rats’ hepatocytes would have an increased rate of glycogenolysis.
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[each_answer] => A. The hepatocytes would have a reduced rate of gluconeogenesis.
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[each_answer] => B. The hepatocytes would have an increased rate of glycolysis.
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[each_answer] => C. The hepatocytes would have an increased rate of glycogenolysis.
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[each_answer] => D. The hepatocytes would have a reduced rate of lipolysis.
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[553957|1] => C
[553957|2] => D
[553957|3] => B
[553957|4] => B
[553957|5] => C
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