Transcript Mechanism of Metformin Action

PHM142 Fall 2016
Instructor: Dr. Jeffrey Henderson
Mechanism of Metformin Action
Katherine Jin, Avery Loi, Laurel Ho, Sarah Huang
November 23rd, 2016
Metformin
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Oral hypoglycemic
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Brand names: Fortamet®, Glucophage®,
Glumetza®, and Riomet®
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First-line treatment as monotherapy or in
combination with other drugs to treat Type 2
Diabetes
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Also used as a pre-treatment for people with high
risk of developing Type 2 Diabetes
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Helps control the amount of glucose in your blood
by decreasing the amount of glucose absorbed
C2H7N5
The Relationship Between Diabetes and Metformin
Metformin is the first line of treatment for type II diabetes
Type I diabetes is an autoimmune disease- 5-10%
No insulin released into body→ sugar buildup in the blood
Can only be treated by giving insulin to the patient
Type II diabetes is due to the body not properly utilizing the insulin that is being
released.- 90%
Insulin present in the body→ insulin resistance in insulin receptors in tissues→ sugar buildup in the
blood
Along with a controlled diet, metformin can be used to treat patients with type II
diabetes by improving sensitivity of body tissues to insulin and lowering glucose
Side and Adverse Effects
Gastrointestinal symptoms (nausea, vomiting and diarrhea)
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Exact mechanism unknown, but several hypotheses
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Release of 5HT (serotonin) in the intestine is associated with nausea, vomiting and diarrhea
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Metformin induces 5HT3 receptor independent release of 5HT (serotonin) from human intestinal
mucosa cells via neuronal and non-neuronal mechanisms
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Most symptoms disappear after 2-3 weeks and occur less often if it is taken with food
Malabsorption of B12
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B12/Intrinsic Factor complex is uptaken by ileal cell membrane receptors that are calcium dependent
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Metformin affects the calcium dependent membrane action
Side and Adverse Effects
Metformin-associated Lactic Acidosis (MALA)
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Lactate is usually used by the liver as part of gluconeogenesis but metformin inhibits this
process
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Allows for buildup of lactic acid in the blood, which can cause acidosis by decreasing the pH
of the blood
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Rare but potentially fatal
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In a Saskatchewan study from 1980-1995, they concluded that the incidence rate of MALA
was 9 per 100,000 person years
Overview of Type II Diabetes and Metformin
Mechanism
Not fully understood, widely agreed that it involves AMP-activated protein kinase
(AMPK)
Multisubunit enzyme involved in protein kinase A cascade
Major cellular regulator of energy metabolism in response to low ATP
AMPK activation
Positive regulation of pathways that replenish cellular ATP (fatty acid oxidation, autophagy)
Negative regulation of pathways that consume ATP (gluconeogenesis, lipid synthesis)
Done through direct phosphorylation of enzymes, transcription factors, coactivators and
corepressors involved in these processes
Mechanism
Metformin promotes insulin-stimulated
glucose uptake through AMPK activation
In the liver, metformin inhibits gluconeogenesis
Regulates hepatic glucose output by inhibiting
mitochondrial respiratory chain complex 1
Inhibits oxidative phosphorylation and
decreases main energy supply of ATP for
hepatocytes
Overall decreased gluconeogenesis in the liver,
as it requires ATP
Mechanism
When ATP levels decline, AMP levels increase
Metformin activates AMPK in an indirect manner
through increase in AMP:ATP ratios in the body
AMPK activation requires binding of AMP to regulatory
sites on the ɣ subunits
Upon activation, AMPK switches body from
Anabolic ATP consuming state → catabolic ATP producing
state
Glucose synthesis and cell growth inhibited
Fatty acid oxidation and glucose uptake stimulated
Mechanism
AMP also an allosteric inhibitor of fructose-1,6-bisphosphate
Key enzyme in gluconeogenesis, so with high AMP → inhibit gluconeogenesis
Recent studies shown that AMP may be key player in modulating glucose output
Compare use of:
AMP mimetic (AICAR) on AMPK
AMPK activator (A-769662)
Binds AMPK allosterically at different site than AMP
Results demonstrated that only the former elicited suppressed glucose output
Mechanism
Metformin also effective for treating diabetes through role as an insulin sensitizer
Leads to reduction in insulin resistance and increase in insulin sensitivity
Enhances peripheral glucose uptake
phosphorylation
of GLUT4 enhancer
factor fatty liver disease
Also shownInducing
to increase
lipid metabolism
to improve
Through AMPK activation, metformin reduces hepatic lipid content
Inhibiting phosphorylation and thus inactivating acetyl CoA carboxylase
Important enzyme for synthesis of malonyl-CoA which is important precursor for synthesis of
fatty acids and inhibitor of mitochondrial fatty acid oxidation
Results in reduced triglyceride levels
Summary
Type I diabetes is due to immune-mediated insulin deficiency
Metformin used to increase insulin sensitivity and helps the body tissues use insulin
more effectively & lowering glucose production in the liver
Metformin is the first line of treatment for type II diabetes
Activates AMPK indirectly
AMPK is a cellular regulator of energy metabolism
Activated AMPK inhibits glucose synthesis (gluconeogenesis) and increases glucose
uptake
Metformin increases the AMP:ATP ratio
References
AMPK Signaling Pathway. (2006, April). Retrieved November 21, 2016, from
https://www.cellsignal.com/common/content/content.jsp?id=pathways-ampk
Bauman, W.A., Shaw, S., Jayatilleke, E., Spungen, A.M., & Herbert, V. (2000). Increased intake of calcium reverses
vitamin B12 malabsorption induced by metformin. Diabetes Care, 23(9), 1227-1231. doi:10.2337/diacare.23.9.1227
Cubeddu, L., Bönisch, H., Göthert, M., Molderings, G., Racké, K., Ramadori, G., . . . Schwörer, H. (2000). Effects of
metformin on intestinal 5-hydroxytrytamine (5-HT) release and on 5-HT receptors. Naunyn-Schmiedeberg’s
Archives of Pharmacology, 361(1), 85-91. doi:10.1007/s002109900152
Liu, K.W. (2006). Metformin-related vitamin B12 deficiency. Age and Ageing, 35(2), 200-201.
doi:10.1093/ageing/afj042
Metformin: MedlinePlus Drug Information. (n.d.). Retrieved 13 November 2016, from
https://medlineplus.gov/druginfo/meds/a696005.html
References (contd.)
Nakano, M., & Inui, A. (2012, January 4). Metformin and incretin-based therapies up-regulate central and
peripheral Adenosine monophosphate-activated protein affecting appetite and metabolism. Indian Journal of
Endocrinology and Metabolism, 16(9), 529. doi:10.4103/2230-8210.105567
Rena, G, Ewan, P. R., Sakamoto, K. (2013).Molecular mechanism of action of metformin: old or new insights?
Diabetologia, 56, 1899-1909. doi: 10.1007/s00125-013-2991-0
Stang, M., Wysowski, D.K., & Butler-Jones, D. (1999). Incidence of lactic acidosis in metformin users. Diabetes
Care, 22(6), 925-927. doi: 10.2337/diacare.22.6.925
Types of Diabetes. (2016). Canadian Diabetes Association. Retrieved 22 November 2016, from
http://www.diabetes.ca/about-diabetes/types-of-diabetes
Viollet, B, Guigas, B, Garcia N.S., Leclerc, J, Foretz, M, Andreelli, F (2012). Cellular and molecular mechanisms
of metformin: an overview. Journal of Clinical Science, 122(6), 253-270. doi: 10.1042/CS20110386.