Metformin raises hydrogen sulfide tissue concentrations in various mouse organs

doi:10.1016/S1734-1140(13)71053-3

Pharmacological Reports

Volume 65, Issue 3, May–June 2013, Pages 737-742

https://doi.org/10.1016/S1734-1140(13)71053-3 Get rights and content

Abstract

Background

The epidemic of diabetes mellitus type 2 forces to intensive work on the disease medication. Metformin, the most widely prescribed insulin sensitizer, exerts pleiotropic actions on different tissues by not fully recognized mechanisms. Hydrogen sulfide (H₂S) is involved in physiology and pathophysiology of various systems in mammals and is perceived as a potential agent in the treatment of different disorders. The interaction between biguanides and H₂S is unknown. The aim of the study is to assess the influence of metformin on the H₂S tissue concentrations in different mouse organs.

Methods

Adult SJL female mice were administered intraperitoneally 100 mg/kg b.w. per day of metformin (group D1, n = 6) or 200 mg/kg b.w. per day of metformin (group D2, n = 7). The control group (n = 6) received physiological saline. The measurements of the free and acid-labile H₂S tissue concentrations were performed with Siegel spectrophotometric modified method.

Results

There was a significant progressive increase in the H₂S concentration along with the rising metformin doses as compared to the control group in the brain (D1 by 103.6%, D2 by 113.5%), in the heart (D1 by 11.7%, D2 by 27.5%) and in the kidney (D1 by 7.1%, D2 by 9.6%). In the liver, massive H₂S accumulation was observed in the group D1 (increase by 420.4%), while in the D2 group only slight H₂S level enhancement was noted (by 12.5%).

Conclusion

Our experiment has shown that metformin administration is followed by H₂S tissue concentrations increase in mouse brain, heart, kidney and liver.

Introduction

The prevalence of diabetes is distressingly increasing, affecting over 340 millions people worldwide to date, and has great social and economical repercussions [2]. The biguanide metformin is the most widely prescribed insulin sensitizer and the drug of choice in most of type 2 diabetic patients [1]. The pleiotropic actions of metformin exceed the glucose production and utilization regulation and concern other cardiometabolic abnormalities commonly met in type 2 diabetes by the mechanisms that are not fully understood [6, 16]. Recent years studies have promoted hydrogen sulfide (H₂S) from a dangerous industrial and environmental toxin to a crucial co-regulator of various physiological processes in mammals [15]. Moreover, H₂S has been also shown to be involved in the development of different clinical disorders with a perspective of H₂S-based agents to be used in the treatment of cardiovascular and other systems’ diseases in the near future [19, 26].

H₂S has been shown to have a protective role in diabetes including i.a. the prevention of pancreatic β cells from apoptosis, antioxidative properties and antiatherogenic effects [27]. Noteworthy, the action of H₂S in diabetes pathophysiology is highly complex and not always clearly beneficial what can be illustrated by the result of the research on insulin sensitivity. In the study of Manna and Jain, H₂S caused an increase in phosphatidylinositol- 3,4,5-trisphosphate (PIP3) and activating phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinase (AKT) in 3T3L1 adipocytes what promoted glucose utilization [20]. In the experiment of Feng et al., PI3K pathway was involved in the inhibitory effect of H₂S on glucose uptake in rat adipocytes [8]. On the contrary, Patel and Shah concluded that H₂S does not have any role in the development of insulin resistance in Wistar rats [24].

The interaction between biguanides and the endogenous H₂S is unknown. The aim of the study is to assess the influence of metformin on the endogenous tissue H₂S concentrations in mouse brain, heart, kidney and liver.

Section snippets

Animals

Nineteen SJL female mice (7-week-old individuals) of approximate 20 g weight were involved in the study. The animals were housed under standard laboratory conditions and had free access to water and food. They were kept at temperature of 22–24°C with a light/dark cycle of 12 h (8 a.m. – 8 p.m. and 8 p.m. – 8 a.m., respectively).

Study design

The study protocol comprised intraperitoneal injections of metformin (Formetic, Polpharma, Poland) dissolved in a saline solution in doses of 2 mg of metformin (100 mg per

Results and Disussion

Acknowledgment:

The study was supported by the grant from Jagiellonian University Medical College No. K/ZBW/000175.

Conflict of interests

None declared.

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Short communicationMetformin raises hydrogen sulfide tissue concentrations in various mouse organs

Abstract

Background

Methods

Results

Conclusion

Introduction

Section snippets

Animals

Study design

Results and Disussion

Acknowledgment:

Transplant Proc

J Biol Chem

Biochem Biophys Res Commun

Neuropharmacology

Int J Cardiol

Pharmacol Rep

Pharmacol Ther

J Biol Chem

Anal Biochem

J Am Coll Cardiol

J Thorac Cardiovasc Surg

J Pharmacol Sci

Pharmacol Rep

Association AD: Standards of medical care in diabetes- 2012

Diabetes Care

Metformin prevents the development of acute lipid-induced insulin resistance in the rat through altered hepatic signaling mechanisms

Diabetes

Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase

Diabetes

Metformin prevents high-glucose-induced endothelial cell death through a mitochondrial permeability transition-dependent process

Diabetes

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome

Eur J Endocrinol

Hydrogen sulfide as a gasotransmitter

J Neurochem

Hydrogen sulfide mitigates transition from compensatory hypertrophy to heart failure

J Appl Physiol

10-year follow-up of intensive glucose control in type 2 diabetes

N Engl J Med

Short communication
Metformin raises hydrogen sulfide tissue concentrations in various mouse organs