Abstract
Original language | English |
---|---|
Pages (from-to) | 1423-1433 |
Number of pages | 11 |
Journal | Diabetes |
Volume | 61 |
Issue number | 6 |
DOIs | |
Publication status | Published - Jun 2012 |
Keywords
- Adenylate Kinase
- Animals
- Cell Line
- Cells, Cultured
- Chelating Agents
- Copper
- Glucose
- Hepatocytes
- Hypoglycemic Agents
- Metformin
- Oxygen Consumption
- Phosphorylation
- Rats
- Ribosomal Protein S6 Kinases
- Signal Transduction
- Trientine
Cite this
}
Cellular Responses to the Metal-Binding Properties of Metformin. / Logie, Lisa; Harthill, Jean; Patel, Kashyap; Bacon, Sandra; Hamilton, D. Lee; Macrae, Katherine; McDougall, Gordon; Wang, Huan-Huan; Xue, Lin; Jiang, Hua; Sakamoto, Kei; Prescott, Alan R.; Rena, Graham (Lead / Corresponding author).
In: Diabetes, Vol. 61, No. 6, 06.2012, p. 1423-1433.Research output: Contribution to journal › Article
TY - JOUR
T1 - Cellular Responses to the Metal-Binding Properties of Metformin
AU - Logie, Lisa
AU - Harthill, Jean
AU - Patel, Kashyap
AU - Bacon, Sandra
AU - Hamilton, D. Lee
AU - Macrae, Katherine
AU - McDougall, Gordon
AU - Wang, Huan-Huan
AU - Xue, Lin
AU - Jiang, Hua
AU - Sakamoto, Kei
AU - Prescott, Alan R.
AU - Rena, Graham
PY - 2012/6
Y1 - 2012/6
N2 - In recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this article, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive p-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action.
AB - In recent decades, the antihyperglycemic biguanide metformin has been used extensively in the treatment of type 2 diabetes, despite continuing uncertainty over its direct target. In this article, using two independent approaches, we demonstrate that cellular actions of metformin are disrupted by interference with its metal-binding properties, which have been known for over a century but little studied by biologists. We demonstrate that copper sequestration opposes known actions of metformin not only on AMP-activated protein kinase (AMPK)-dependent signaling, but also on S6 protein phosphorylation. Biguanide/metal interactions are stabilized by extensive p-electron delocalization and by investigating analogs of metformin; we provide evidence that this intrinsic property enables biguanides to regulate AMPK, glucose production, gluconeogenic gene expression, mitochondrial respiration, and mitochondrial copper binding. In contrast, regulation of S6 phosphorylation is prevented only by direct modification of the metal-liganding groups of the biguanide structure, supporting recent data that AMPK and S6 phosphorylation are regulated independently by biguanides. Additional studies with pioglitazone suggest that mitochondrial copper is targeted by both of these clinically important drugs. Together, these results suggest that cellular effects of biguanides depend on their metal-binding properties. This link may illuminate a better understanding of the molecular mechanisms enabling antihyperglycemic drug action.
KW - Adenylate Kinase
KW - Animals
KW - Cell Line
KW - Cells, Cultured
KW - Chelating Agents
KW - Copper
KW - Glucose
KW - Hepatocytes
KW - Hypoglycemic Agents
KW - Metformin
KW - Oxygen Consumption
KW - Phosphorylation
KW - Rats
KW - Ribosomal Protein S6 Kinases
KW - Signal Transduction
KW - Trientine
UR - http://www.scopus.com/inward/record.url?scp=84861887451&partnerID=8YFLogxK
U2 - 10.2337/db11-0961
DO - 10.2337/db11-0961
M3 - Article
C2 - 22492524
VL - 61
SP - 1423
EP - 1433
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 6
ER -