Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
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Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. / Hunter, Roger W.; Hughey, Curtis C.; Lantier, Louise; Sundelin, Elias I.; Peggie, Mark; Zeqiraj, Elton; Sicheri, Frank; Jessen, Niels; Wasserman, David H.; Sakamoto, Kei.
I: Nature Medicine, Bind 24, Nr. 9, 01.09.2018, s. 1395-1406.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase
AU - Hunter, Roger W.
AU - Hughey, Curtis C.
AU - Lantier, Louise
AU - Sundelin, Elias I.
AU - Peggie, Mark
AU - Zeqiraj, Elton
AU - Sicheri, Frank
AU - Jessen, Niels
AU - Wasserman, David H.
AU - Sakamoto, Kei
PY - 2018/9/1
Y1 - 2018/9/1
N2 - Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5′-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet–fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
AB - Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5′-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet–fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
U2 - 10.1038/s41591-018-0159-7
DO - 10.1038/s41591-018-0159-7
M3 - Journal article
C2 - 30150719
AN - SCOPUS:85052990530
VL - 24
SP - 1395
EP - 1406
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 9
ER -
ID: 238433199