Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes

Author(s): Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI


Background: Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.

Methods: We performed hyperinsulinemic-euglycemic clamp studies in combination with infusions of [6,6-(2)H(2)]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton ((1)H) magnetic resonance spectroscopy studies were performed to measure intramyocellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [(2)H(5)]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed (31)P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle.

Results: The insulin-stimulated rate of glucose uptake by muscle was approximately 60 percent lower in the insulin-resistant subjects than in the insulin-sensitive control subjects (P<0.001) and was associated with an increase of approximately 80 percent in the intramyocellular lipid content (P=0.005). This increase in intramyocellular lipid content was most likely attributable to mitochondrial dysfunction, as reflected by a reduction of approximately 30 percent in mitochondrial phosphorylation (P=0.01 for the comparison with controls), since there were no significant differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor alpha, interleukin-6, resistin, or adiponectin.

Conclusions: These data support the hypothesis that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.

Similar Articles

Membranes as possible pacemakers of metabolism

Author(s): Hulbert AJ, Else PL

Life, death and membrane bilayers

Author(s): Hulbert AJ

Quantitative atomic force microscopy with carbon monoxide terminated tips

Author(s): Sun Z, Boneschanscher MP, Swart I, Vanmaekelbergh D, Liljeroth P

Structure of lipid bilayers

Author(s): Nagle JF, Tristram-Nagle S

The cellular fate of glucose and its relevance in type 2 diabetes

Author(s): Bouché C, Serdy S, Kahn CR, Goldfine AB

Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes

Author(s): Kelley DE, He J, Menshikova EV, Ritov VB

Relationship between carnitine, fatty acids and insulin resistance

Author(s): Lohninger A, Radler U, Jinniate S, Lohninger S, Karlic H, et al.

Is irisin a human exercise gene? Nature 488: E9-10

Author(s): Timmons JA, Baar K, Davidsen PK, Atherton PJ

FNDC5 and irisin in humans: I

Author(s): Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, et al.

MR properties of brown and white adipose tissues

Author(s): Hamilton G, Smith DL Jr, Bydder M, Nayak KS, Hu HH

Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance

Author(s): Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, et al.

Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin

Author(s): Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, et al.

Hemorheological disorders in diabetes mellitus

Author(s): Cho YI, Mooney MP, Cho DJ

Modulation of the bilayer thickness of exocytic pathway membranes by membrane proteins rather than cholesterol

Author(s): Mitra K, Ubarretxena-Belandia I, Taguchi T, Warren G, Engelman DM