Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
To further explore the nature of the mitochondrial dysfunction and insulin resistance that occur in the muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured mitochondrial content by electron microscopy and insulin signaling in muscle biopsy samples obtained from these individuals before and during a hyperinsulinemic-euglycemic clamp. The rate of insulin-stimulated muscle glucose uptake was approximately 60% lower in the IR offspring than the control subjects and was associated with an approximately 60% increase in the intramyocellular lipid content as assessed by H magnetic resonance spectroscopy. Muscle mitochondrial density was 38% lower in the IR offspring. These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. These data provide new insights into the earliest defects that may be responsible for the development of type 2 diabetes and support the hypothesis that reductions in mitochondrial content result in decreased mitochondrial function, which predisposes IR offspring to intramyocellular lipid accumulation, which in turn activates a serine kinase cascade that leads to defects in insulin signaling and action in muscle.
Morino
Katsutaro
K
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06536-8012, USA.
Petersen
Kitt Falk
KF
Dufour
Sylvie
S
Befroy
Douglas
D
Frattini
Jared
J
Shatzkes
Nadine
N
Neschen
Susanne
S
White
Morris F
MF
Bilz
Stefan
S
Sono
Saki
S
Pypaert
Marc
M
Shulman
Gerald I
GI
D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D015992:Body Mass Index; D001835:Body Weight; D004272:DNA, Mitochondrial / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism*; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006801:Humans; D006946:Hyperinsulinism; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008055:Lipids / Q000737:chemistry; D008297:Male; D008854:Microscopy, Electron; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009132:Muscles / Q000473:pathology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; D004272:DNA, Mitochondrial; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008055:Lipids; D010750:Phosphoproteins; D012333:RNA, Messenger; D014280:Triglycerides; D012694:Serine; D017346:Protein Serine-Threonine Kinases