S-adenosyl-L-methionine increases skeletal muscle mitochondrial DNA density and whole body insulin sensitivity in OLETF rats.
Both mitochondrial dysfunction and alterations in mitochondrial DNA (mtDNA) are implicated in type 2 diabetes mellitus and insulin resistance. Evidence also suggests that metabolism of S-adenosyl-L-methionine (SAM), the universal methyl donor for biological methylation, is associated with mitochondrial dysfunction and insulin resistance. We investigated the effect of SAM on mtDNA density and insulin sensitivity using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of type 2 diabetes mellitus and insulin resistance. To determine the short-term effect on mtDNA density, SAM (15 mg.kg-1.d-1) was administered intraperitoneally for 7 d to 6 male, 57-wk-old OLETF rats and 6 Long-Evans Tokushima Otsuka (LETO) rats of the same age as a nondiabetic control. To determine the long-term effect, the same dose of SAM was administered daily to 5 male, 6-wk-old OLETF rats until the age of 25 wk; 7 control OLETF rats received vehicle and 7 LETO rats were untreated. Skeletal muscle mtDNA density was measured by either competitive or multiplex PCR and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. SAM treatment for 1 wk increased skeletal muscle mtDNA density of both OLETF and LETO rats. The long-term SAM treatment significantly reduced body weight gain as well as increased skeletal muscle mtDNA density and whole body insulin sensitivity in OLETF rats compared with their vehicle-treated controls. Furthermore, in all 3 groups, skeletal muscle mtDNA density correlated with insulin sensitivity (r=0.752, P<0.001). In conclusion, SAM treatment increased mtDNA density in the skeletal muscle, improved whole body insulin sensitivity, and prevented body weight gain in OLETF rats.
Jin
Cheng Ji
CJ
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-744, Korea.
Park
Hyeong Kyu
HK
Cho
Young Min
YM
Pak
Youngmi Kim
YK
Lee
Ki-Up
KU
Kim
Min Seon
MS
Friso
Simonetta
S
Choi
Sang-Woon
SW
Park
Kyong Soo
KS
Lee
Hong Kyu
HK
D000375:Aging; D000818:Animals; D004247:DNA / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005247:Feeding Behavior; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology*; D051381:Rats; D020334:Rats, Inbred OLETF; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D015430:Weight Gain
D007328:Insulin; D012436:S-Adenosylmethionine; D004247:DNA; D005947:Glucose