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MCAT

Unit 2: Lesson 1

Foundation 1: Biomolecules

Cellular effects of metformin, a drug for diabetes mellitus

Problem

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.
Which statement about Compound K is most likely to be true?
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