Administration of Melatonin and Metformin Prevents Deleterious Effects of Circadian Disruption and Obesity in Male Rats

Thomas, Anthony P.; Hoang, Jonathan D.; Vongbunyong, Kenny; Nguyen, Andrew H.; Rakshit, Kuntol; Matveyenko, Aleksey V.

doi:10.1210/en.2016-1309

Cited by 42 publications

(39 citation statements)

References 67 publications

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“…Recently, Thomas et al studied rats concomitantly exposed to circadian disruption and diet‐induced obesity and receiving daily oral gavage treatment with 20 mg/kg of melatonin. They showed that melatonin improved circadian activity rhythms, attenuated beta‐cell failure, and enhanced glucose tolerance . Interestingly, the benefit on metabolism was evident especially at circadian time 4, which corresponds to the pacific standard time of 10 am .…”

Section: Discussionmentioning

confidence: 99%

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Heo

Yoon

et al. 2018

Journal of Pineal Research

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Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The α2-HS-glycoprotein gene (AHSG) and its protein, fetuin-A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA-dependent manner. In HepG2 cells treated with 300 μmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 μmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA-overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid-induced ER stress markers, CHOP, Bip, ATF-6, XBP-1, ATF-4, and PERK. In addition, in the high-fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one-third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p-AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression.

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Section: Discussionmentioning

confidence: 99%

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Heo

Yoon

et al. 2018

Journal of Pineal Research

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“…41 Antioxidants properties of the combination of metformin and melatonin have been established in rats with induced polycystic ovary syndrome. By contrast, the combined treatment tends to ameliorate insulin sensitivity compared to metformin alone, especially during the late phase of rising glycaemia.…”

Section: Effects Of Melatonin In Combination With Metformin On Glucmentioning

confidence: 99%

Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high‐fat‐fed rats

Dantas-Ferreira

Raingard

Dumont

et al. 2018

Endocrino Diabet & Metabol

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Summary Background Melatonin is a hormone synthesized mainly by the pineal gland, and secreted only at night. Melatonin has been proposed as a modulator of glucose metabolism. Methods Here we studied the metabolic effects of melatonin administration alone (s.c. 10 mg/kg) or in combination with metformin (p.o. 300 mg/kg), a widely used anti‐diabetic drug. These treatments were tested on glucose tolerance, insulin sensitivity and food intake in Zucker fatty rats (i.e., bearing a missense mutation in the leptin receptor gene) and high‐fat fed Sprague‐Dawley rats. Results Melatonin alone or in combination did not significantly modify glucose tolerance in either model. Melatonin alone in high‐fat fed Sprague‐Dawley improved insulin sensitivity to the level of metformin. In addition, combined treatment further ameliorated insulin sensitivity (+13%), especially during the late phase of rising glycemia. The lack of similar effects in Zucker rats suggests an involvement of leptin signaling in mediating the positive effects of melatonin. Body mass gain in Sprague‐Dawley rats was decreased by both metformin, and combined metformin and melatonin. While melatonin alone did not markedly affect food intake, its combination with metformin led to a more pronounced anorexia (‐17% food intake during the last week), as compared to metformin alone. Conclusions Melatonin improves the beneficial effects of metformin on insulin sensitivity and body mass gain in high‐fat fed Sprague‐Dawley rats. Therefore, the combination of melatonin and metformin could be beneficial to develop dual therapies to treat or delay type 2 diabetes associated with obesity.

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“…Circadian disruption and obesity synergize to predispose to development of Type 2 diabetes (T2DM), signifying that therapeutic targeting of both circadian and metabolic dysfunctions should be considered as a potential treatment approach [5].…”

Section: Introductionmentioning

confidence: 99%

Influence of melatonin on carbohydrate metabolism in the kidney of alloxan diabetic rats

Kushnir¹,

Yaremii²,

Shvets³

et al. 2017

Fiziol Zh

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Administration of Melatonin and Metformin Prevents Deleterious Effects of Circadian Disruption and Obesity in Male Rats

Cited by 42 publications

References 67 publications

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha‐2‐HS‐glycoprotein

Melatonin potentiates the effects of metformin on glucose metabolism and food intake in high‐fat‐fed rats

Influence of melatonin on carbohydrate metabolism in the kidney of alloxan diabetic rats

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