Metformin has been used for nearly a century and is now the most widely prescribed oral anti-diabetic agent worldwide. Yet how metformin acts remains only partially understood and controversial. One ...key reason may be that almost all previous studies were conducted with supra-pharmacological concentrations (doses) of metformin, 10–100 times higher than maximally achievable therapeutic concentrations found in patients with type 2 diabetes mellitus.
Metformin is a first-line agent for treating patients with type 2 diabetes mellitus; however, its mechanism of action remains controversial. In this Essay, He and Wondisford discuss proposed mechanisms and raise awareness that studies employing supra-physiologic concentrations (doses) of metformin should be interpreted with caution.
Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients’ ...hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5′ AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin’s anti-tumor effects.
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•Clinically relevant metformin dose improves liver mitochondrial respiration in obesity•Pharmacological metformin increases mitochondrial respiration and fission•Supra-pharmacological metformin inhibits mitochondrial activity by ADP reduction•AMPK is required for metformin suppression of liver glucose production
The mechanism of metformin action still remains controversial, in particular on mitochondrial activity and the involvement of AMPK. Wang et al. show that pharmacological metformin concentration or dose improves mitochondrial respiration by increasing mitochondrial fission through AMPK-Mff signaling; in contrast, supra-pharmacological metformin concentrations reduce mitochondrial respiration through decreasing adenine nucleotide levels.
Abstract
Current literature makes a distinction between two pathways for thyroid hormone signaling: genomic and nongenomic. However, this classification is a source of confusion. We propose a ...clarification in the nomenclature that may help to avoid unproductive controversies and favor progress in this field of research. Four types of thyroid hormone signaling are defined, and the experimental criteria for classification are discussed.
A classification of thyroid hormone signaling into four distinct types is proposed, to replace the confusing “genomic” vs “nongenomic” designation.
Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients ...with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.
Gluconeogenesis is a critical biosynthetic process that helps maintain whole-body glucose homeostasis and becomes altered in certain medical diseases. We review gluconeogenic flux in various medical ...diseases, including common metabolic disorders, hormonal imbalances, specific inborn genetic errors, and cancer. We discuss how the altered gluconeogenic activity contributes to disease pathogenesis using data from experiments using isotopic tracer and spectroscopy methodologies. These in vitro, animal, and human studies provide insights into the changes in circulating levels of available gluconeogenesis substrates and the efficiency of converting those substrates to glucose by gluconeogenic organs. We highlight ongoing knowledge gaps, discuss emerging research areas, and suggest future investigations. A better understanding of altered gluconeogenesis flux may ultimately identify novel and targeted treatment strategies for such diseases.
Unlike other thyroid hormone receptors (THRs), the beta 2 isoform (THRB2) has a restricted expression pattern and is uniquely and abundantly phosphorylated at a conserved serine residue S101 (S102 in ...humans). Using tagged and or phosphorylation-defective (S101A) THRB2 mutant mice, we show that THRB2 is present in a large subset of POMC neurons and mitigates ROS accumulation during ROS-triggering events, such as fasting/refeeding or high fat diet (HFD). Excessive ROS accumulation in mutant POMC neurons was accompanied by a skewed production of orexigenic/anorexigenic hormones, resulting in elevated food intake. The prolonged exposure to pathogenic hypothalamic ROS levels during HFD feeding lead to a significant loss of POMC neurons in mutant versus wild-type (WT) mice. In cultured cells, the presence of WT THRB2 isoform, but not other THRs, or THRB2
, reduced ROS accumulation upon exogenous induction of oxidative stress by tert-butyl hydroperoxide. The protective function of phospho-THRB2 (pTHRB2) did not require thyroid hormone (TH), suggesting a TH-independent role of the THRB2 isoform, and phospho-S101 in particular, in regulating oxidative stress. We propose that pTHRB2 has a fundamental role in neuronal protection against ROS cellular damage, and mitigates hypothalamic pathological changes found in diet-induced obesity.
Metformin is the most widely prescribed oral anti-diabetic agent. Recently, we have shown that low metformin concentrations found in the portal vein suppress glucose production in hepatocytes through ...activation of AMPK. Moreover, low concentrations of metformin were found to activate AMPK by increasing the phosphorylation of AMPKα at Thr-172. However, the mechanism underlying the increase in AMPKα phosphorylation at Thr-172 and activation by metformin remains unknown. In the current study, we find that low concentrations of metformin promote the formation of the AMPK αβγ complex, resulting in an increase in net phosphorylation of the AMPK α catalytic subunit at Thr-172 by augmenting phosphorylation by LKB1 and antagonizing dephosphorylation by PP2C.
Background: The mechanism underlying the activation of AMPK by metformin remains unclear.
Results: Metformin promotes the formation of AMPK αβγ heterotrimeric complex.
Conclusion: The formation of the AMPK αβγ heterotrimeric complex augments AMPKα phosphorylation by LKB1 and prevents dephosphorylation by protein phosphatase.
Significance: Metformin-mediated formation of the AMPK αβγ heterotrimeric complex results in AMPK activation by elevating AMPK phosphorylation at Thr-172.
Tracking the carbons supplying gluconeogenesis Shah, Ankit M.; Wondisford, Fredric E.
Journal of biological chemistry/The Journal of biological chemistry,
10/2020, Volume:
295, Issue:
42
Journal Article
Peer reviewed
Open access
As the burden of type 2 diabetes mellitus (T2DM) grows in the 21st century, the need to understand glucose metabolism heightens. Increased gluconeogenesis is a major contributor to the hyperglycemia ...seen in T2DM. Isotope tracer experiments in humans and animals over several decades have offered insights into gluconeogenesis under euglycemic and diabetic conditions. This review focuses on the current understanding of carbon flux in gluconeogenesis, including substrate contribution of various gluconeogenic precursors to glucose production. Alterations of gluconeogenic metabolites and fluxes in T2DM are discussed. We also highlight ongoing knowledge gaps in the literature that require further investigation. A comprehensive analysis of gluconeogenesis may enable a better understanding of T2DM pathophysiology and identification of novel targets for treating hyperglycemia.
Metformin is a first-line antidiabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that ...suppression of glucose production in hepatocytes by metformin is AMPK-independent; however, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60–80 μm). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation at Ser-485/497 on the α subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy.
Background: Whether suppression of glucose production by metformin is through AMPK-dependent inhibition of gluconeogenic gene expression remains controversial.
Results: Metformin inhibits gluconeogenic gene expression in hepatocytes.
Conclusion: Low metformin concentrations found in the portal vein suppress glucose production via AMPK-dependent mechanism.
Significance: The hyperglucagonemia of diabetes mellitus decreases metformin suppression of glucose production through a PKA-mediated phosphorylation of the AMPK α subunit at Ser-485/497.
Fasting induces profound changes in the hypothalamic-pituitary-thyroid (HPT) axis. After binding thyroid hormone (TH), the TH receptor beta 2 isoform (THRB2) represses
and
subunit genes and is the ...principle negative regulator of the HPT axis. Using mass spectrometry, we identified a major phosphorylation site in the AF-1 domain of THRB2 (serine 101, S101), which is conserved among many members of the nuclear hormone receptor superfamily. More than 50% of THRB2 is phosphorylated at S101 in cultured thyrotrophs (TαT1.1) and in the mouse pituitary. All other THR isoforms lack this site and exhibit limited overall levels of phosphorylation. To determine the importance of THRB2 S101 phosphorylation, we used the TαT1.1 cell line and S101A mutant knock-in mice (
). We found that TH promoted S101 THRB2 phosphorylation and was essential for repression of the axis at physiologic TH concentrations. In mice, THRB2 phosphorylation was also increased by fasting and mimicked
and
repression by TH. In vitro studies demonstrated that a master metabolic sensor, AMP-activated kinase (AMPK) induced phosphorylation at the same site and caused
repression independent of TH. Furthermore, we identified cyclin-dependent kinase 2 (CDK2) as a direct kinase phosphorylating THRB2 S101 and propose that AMPK or TH increase S101 phosphorylation through the activity of CDK2. This study provides a physiologically relevant function for THR phosphorylation, which permits nutritional deprivation and TH to use a common mechanism for acute suppression of the HPT axis.
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