Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents - PubMed (original) (raw)

. 2005 Dec;115(12):3587-93.

doi: 10.1172/JCI25151. Epub 2005 Nov 10.

Kitt Falk Petersen, Sylvie Dufour, Douglas Befroy, Jared Frattini, Nadine Shatzkes, Susanne Neschen, Morris F White, Stefan Bilz, Saki Sono, Marc Pypaert, Gerald I Shulman

Affiliations

Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents

Katsutaro Morino et al. J Clin Invest. 2005 Dec.

Abstract

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.

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Figures

Figure 1

Figure 1

Results of oral glucose tolerance test. Mean plasma concentrations of glucose (A) and insulin (B) before and during a 75-g oral glucose tolerance test in control subjects (n = 6) and IR offspring (n = 8). P = 0.0009 for the comparison of the areas under the curve for insulin concentration of control subjects and IR offspring.

Figure 2

Figure 2

Hyperinsulinemic-euglycemic clamp and intramyocellular lipid content. (A) Insulin-stimulated rates of muscle glucose metabolism in control subjects (n = 6) and IR offspring (n = 8). (B) Intramyocellular lipid content in soleus muscle of control subjects (n = 6) and IR offspring (n = 8), measured by localized 1H MRS.

Figure 3

Figure 3

Mitochondrial density and gene expression data. (A) Mitochondrial density in control subjects (n = 6) and IR offspring (n = 8), assessed by electron microscopy. The pound symbol (#) indicates muscle fiber; the asterisk indicates mitochondrion. (B) Mitochondrial protein expressions assessed by Western blotting in control subjects (n = 6) and IR offspring (n = 9). Results were normalized to β-actin protein expression. SDH, succinate dehydrogenase; PDH, pyruvate dehydrogenase.

Figure 4

Figure 4

mRNA and protein expression of mitochondrial biogenesis genes. (A) mRNA expression of PGC-1 and downstream genes determined by real-time quantitative PCR using a TaqMan probe in control subjects (n = 7) and IR offspring (n = 13). (B) Protein expression of PGC-1α, PGC-1β, and mtTFA measured by Western blotting in control subjects (n = 6) and IR offspring (n = 9). (C) mtDNA copy number was determined by real-time quantitative PCR using a TaqMan probe against NADH dehydrogenase 2 (ND2) and β-actin. mtDNA copy number was calculated as the ratio of ND2 to β-actin in control subjects (n = 7) and IR offspring (n = 9).

Figure 5

Figure 5

Insulin signaling data. (A) IRS-1 serine phosphorylation at Ser307, Ser312, Ser616, and Ser636 in the basal state in control subjects (n = 10) and IR offspring (n = 7). (B) Insulin-stimulated Akt phosphorylation at 20 minutes on Ser473 in control subjects (n = 5) and IR offspring (n = 7). Akt phosphorylation was normalized to total Akt protein expression.

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