scholarly journals Metformin Inhibits Human Androgen Production by Regulating Steroidogenic Enzymes HSD3B2 and CYP17A1 and Complex I Activity of the Respiratory Chain

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4354-4366 ◽  
Author(s):  
Andrea Hirsch ◽  
Dagmar Hahn ◽  
Petra Kempná ◽  
Gaby Hofer ◽  
Jean-Marc Nuoffer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
Respiratory Chain ◽  
Complex I ◽  
Organic Cation ◽  
Polycystic Ovary ◽  
Organic Cation Transporters ◽  
Ovary Syndrome ◽  
Ampk Signaling ◽  
Cation Transporters

Metformin is treatment of choice for the metabolic consequences seen in polycystic ovary syndrome for its insulin-sensitizing and androgen-lowering properties. Yet, the mechanism of action remains unclear. Two potential targets for metformin regulating steroid and glucose metabolism are AMP-activated protein kinase (AMPK) signaling and the complex I of the mitochondrial respiratory chain. Androgen biosynthesis requires steroid enzymes 17α-Hydroxylase/17,20 lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2), which are overexpressed in ovarian cells of polycystic ovary syndrome women. Therefore, we aimed to understand how metformin modulates androgen production using NCI-H295R cells as an established model of steroidogenesis. Similar to in vivo situation, metformin inhibited androgen production in NCI cells by decreasing HSD3B2 expression and CYP17A1 and HSD3B2 activities. The effect of metformin on androgen production was dose dependent and subject to the presence of organic cation transporters, establishing an important role of organic cation transporters for metformin's action. Metformin did not affect AMPK, ERK1/2, or atypical protein kinase C signaling. By contrast, metformin inhibited complex I of the respiratory chain in mitochondria. Similar to metformin, direct inhibition of complex I by rotenone also inhibited HSD3B2 activity. In conclusion, metformin inhibits androgen production by mechanisms targeting HSD3B2 and CYP17-lyase. This regulation involves inhibition of mitochondrial complex I but appears to be independent of AMPK signaling.

scholarly journals Renoprotective Effects of Metformin are Independent of Organic Cation Transporters 1 & 2 and AMP-activated Protein Kinase in the Kidney

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Michael Christensen ◽  
Jonas B. Jensen ◽  
Steen Jakobsen ◽  
Niels Jessen ◽  
Jørgen Frøkiær ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Organic Cation ◽  
Organic Cation Transporters ◽  
Cation Transporters ◽  
Amp Activated Protein Kinase

Defective Activation of Protein Kinase C-ζ in Muscle by Insulin and Phosphatidylinositol-3,4,5,-(PO4)3 in Obesity and Polycystic Ovary Syndrome

2004 ◽  
Vol 2 (1) ◽  
pp. 49-56
Author(s):  
Mary Beeson ◽  
Mini P. Sajan ◽  
Joaquin Gomez-Daspet ◽  
Victor Luna ◽  
Michelle Dizon ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
Kinase C

Defective Activation of Protein Kinase C-z in Muscle by Insulin and Phosphatidylinositol-3,4,5,-(PO4)3in Obesity and Polycystic Ovary Syndrome

2004 ◽  
Vol 2 (1) ◽  
pp. 49-56
Author(s):  
Mary Beeson ◽  
Mini P. Sajan ◽  
Joaquin Gomez Daspet ◽  
Victor Luna ◽  
Michelle Dizon ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
Kinase C

scholarly journals Association study of AMP-activated protein kinase subunit genes in polycystic ovary syndrome

2009 ◽  
Vol 161 (3) ◽  
pp. 405-409 ◽  
Author(s):  
Kari Sproul ◽  
Michelle R Jones ◽  
Ricardo Azziz ◽  
Mark O Goodarzi
Keyword(s):  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
Multiple Testing ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Ovary Syndrome ◽  
Component Traits ◽  
Amp Activated Protein Kinase

ObjectiveTo examine the genes for AMP-activated protein kinase (AMPK) subunits α2 (PRKAA2) and γ3 (PRKAG3) as candidates for polycystic ovary syndrome (PCOS) and its component traits.Design and methodsA total of 287 white PCOS women were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham and 187 white control subjects were recruited from the surrounding community. Seven PRKAA2 single nucleotide polymorphisms (SNPs) and four PRKAG3 SNPs were genotyped in PCOS cases and controls. Genotyping and association analysis were performed at Cedars-Sinai Medical Center.ResultsNominal associations of PRKAA2 variants with insulin-related traits and the PRKAG3 Pro71Ala variant with PCOS were not statistically significant after multiple testing correction. Among PCOS patients, there were no associations between variants in AMPK subunit genes and androgenic or reproductive traits.ConclusionsVariants in genes for AMPKα2 and AMPKγ3 were not associated with PCOS or its component traits. Our evidence does not demonstrate that AMPK is a major genetic risk factor for PCOS.

scholarly journals POTENSI PENGGUNAAN METFORMIN SEBAGAI SUPLEMENTASI DIET PADA OBESITAS

2020 ◽  
Vol 8 (1) ◽  
pp. 38-43
Author(s):  
Harry Salomo
Keyword(s):  
Side Effects ◽  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
World Health Organization ◽  
Polycystic Ovary ◽  
Activity Patterns ◽  
World Health ◽  
Ovary Syndrome ◽  
Health Organization ◽  
Amp Activated Protein Kinase

ABSTRAK  Pendahuluan: Obesitas merupakan kondisi yang disebabkan oleh ketidakseimbaangan energi baik asupan maupun pola aktivitas fisik, dimana menurut World Health Organization (WHO) diartikan sebagai Indeks Massa Tubuh (IMT) ≥30 dan ≥25,00 pada kategori Asia. Obesitas merupakan permasalahan global, lebih lagi di Indonesia sedang terjadi peningkatan drastis, yaitu peningkatan 50% pada laki–laki dan 100% pada perempuan. Obesitas merupakan faktor risiko berbagai macam penyakit. Teori mengenai obesitas dan hiperinsulinemia ini masih menjadi kontroversi di kalangan peneliti tentang mana yang terjadi lebih dahulu, tetapi berdasarkan penelitian diet tinggi lemak mengakibatkan hiperinsulinemia yang lebih lanjut mengakibatkan obesitas. Manapun yang terlebih dahulu, yang jelas terdapat keadaan hiperinsulinemia pada obesitas. Pembahasan: Kondisi hiperinsulinemia ini bisa diinterupsi lebih lanjut dengan obat yang meningkatkan sensitivitas yaitu metformin. Mekanisme kerja metformin sebenarnya belum dipahami penuh, namun terdapat aktivasi AMP-activated Protein Kinase (AMPK) yang lebih lanjut mempengaruhi keseimbangan energi melalui berbagai jalur. Sebagai suplementasi metformin tergolong aman dan telah terbukti pada penggunaan jangka panjang, efek samping yang ditimbulkan biasanya ringan pada saluran pencernaan, efek samping berat asidosis laktat sangat jarang terjadi. Kesimpulan: Penggunaan metformin untuk menangani obesitas sebenarnya sudah sangat luas terutama pada pasien Polycystic Ovary Syndrome (PCOS), dan berbagai penelitian telah menunjukkan penurunan yang tidak besar namun signifikan .  Kata Kunci: AMPK, IMT, obesitas, metformin  ABSTRACT  Introduction: Obesity is a condition caused by energy disruption of both intake and physical activity patterns, which World Health Organization (WHO) defined as Body Mass Index (BMI) ≥30 dan ≥25.00 in Asian category. Obesity is a global problem, moreover in Indonesia there is a drastic increase, about 50% increase in men and 100% in women. Obesity is a risk factor for various diseases. The theory of obesity and hyperinsulinemia is still controversy among researchers about which one is happening first, but based on  studies  high-fat diet leads to hyperinsulinemia which further leads to obesity. Whichever comes first, clearly there is a state of hyperinsulinemia in obesity. Discussion:  This hyperinsulemia condition can be interrupted by drugs that capable to increase the sensitivity of metformin. The mechanism of action of metformin is not yet fully understood, but there is activation of AMP-activated protein kinase (AMPK) which further affects the energy balance through multiple pathways. As metformin supplementation is safe and has been known to be of long-term use, side effects are usually mild on the gastrointestinal tract, and severe side effects of lactic acidosis are very rare. Conclusion: The use of metformin for dealing with obesity has actually been very wide especially in patients with Polycystic Ovary Syndrome (PCOS), and various studies have shown a not great but significant decrease of body weight.  Keywords: AMPK, BMI, obesity, metformin

Vitamin D3 affects mitochondrial biogenesis through mitogen‐activated protein kinase in polycystic ovary syndrome mouse model

2020 ◽  
Vol 235 (9) ◽  
pp. 6113-6126
Author(s):  
Zahra Safaei ◽  
Shabnam Bakhshalizadeh ◽  
Mohammad Hossein Nasr‐Esfahani ◽  
Azadeh Akbari Sene ◽  
Vahid Najafzadeh ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Polycystic Ovary Syndrome ◽  
Mouse Model ◽  
Mitochondrial Biogenesis ◽  
Vitamin D3 ◽  
Polycystic Ovary ◽  
Mitogen Activated Protein Kinase ◽  
Ovary Syndrome ◽  
Mitogen Activated Protein
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