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. 2007 May;4(5):e154.
doi: 10.1371/journal.pmed.0040154.

Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes

Julia Szendroedi  1 , Albrecht I Schmid, Marek Chmelik, Christian Toth, Attila Brehm, Martin Krssak, Peter Nowotny, Michael Wolzt, Werner Waldhausl, Michael Roden
Affiliations

Muscle mitochondrial ATP synthesis and glucose transport/phosphorylation in type 2 diabetes

Julia Szendroedi et al. PLoS Med. 2007 May.

Abstract

Background: Muscular insulin resistance is frequently characterized by blunted increases in glucose-6-phosphate (G-6-P) reflecting impaired glucose transport/phosphorylation. These abnormalities likely relate to excessive intramyocellular lipids and mitochondrial dysfunction. We hypothesized that alterations in insulin action and mitochondrial function should be present even in nonobese patients with well-controlled type 2 diabetes mellitus (T2DM).

Methods and findings: We measured G-6-P, ATP synthetic flux (i.e., synthesis) and lipid contents of skeletal muscle with (31)P/(1)H magnetic resonance spectroscopy in ten patients with T2DM and in two control groups: ten sex-, age-, and body mass-matched elderly people; and 11 younger healthy individuals. Although insulin sensitivity was lower in patients with T2DM, muscle lipid contents were comparable and hyperinsulinemia increased G-6-P by 50% (95% confidence interval [CI] 39%-99%) in all groups. Patients with diabetes had 27% lower fasting ATP synthetic flux compared to younger controls (p = 0.031). Insulin stimulation increased ATP synthetic flux only in controls (younger: 26%, 95% CI 13%-42%; older: 11%, 95% CI 2%-25%), but failed to increase even during hyperglycemic hyperinsulinemia in patients with T2DM. Fasting free fatty acids and waist-to-hip ratios explained 44% of basal ATP synthetic flux. Insulin sensitivity explained 30% of insulin-stimulated ATP synthetic flux.

Conclusions: Patients with well-controlled T2DM feature slightly lower flux through muscle ATP synthesis, which occurs independently of glucose transport /phosphorylation and lipid deposition but is determined by lipid availability and insulin sensitivity. Furthermore, the reduction in insulin-stimulated glucose disposal despite normal glucose transport/phosphorylation suggests further abnormalities mainly in glycogen synthesis in these patients.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Plasma Glucose, Insulin and FFAs
Time course of plasma glucose (top), insulin (middle), and FFAs (bottom) concentrations during euglycemic (approximately 5.5 mM glucose) –hyperinsulinemic (approximately 500 pM insulin) clamps in patients with T2DM (n = 10) (diamonds), age- and BMI-matched controls (CONo; n = 10) (squares), and young healthy controls (CONy; n = 11) (triangles). All units expressed as means ± SD. * p < 0.05 T2DM versus controls.
Figure 2
Figure 2. Glucose Metabolism and Intracellular Lipids of Skeletal Muscle and Liver
Whole-body glucose disposal (A) and ΔEGP (B) during euglycemic–hyperinsulinemic clamp (n = 31). IMCL in skeletal muscle (n = 31) (C) and liver (n = 29) (HCL) (D). Patients with T2DM (black columns), CONo (grey columns), and CONy (white columns). All results are means ± SD. ¶ p < 0.001 T2DM versus CONy; † p < 0.01 CONo versus T2DM and CONy; * p < 0.05 T2DM versus CONy; § p < 0.001 T2DM versus controls.
Figure 3
Figure 3. Rates of ATP Synthetic Flux
Rates of ATP synthetic flux (means ± SD) during fasting (bfATP, full columns) and during insulin stimulation (ifATP, hatched columns). Patients with T2DM (black columns), CONo controls (grey columns) and CONy controls (white columns) (n = 31). § p < 0.05 T2DM versus CONy; *, p < 0.05; †, p < 0.01.
Figure 4
Figure 4. Associations between ATP Synthetic Flux and Metabolic Parameters
Correlation analyses of rates of ATP synthetic flux (n = 31). (A) Relation between fasting plasma concentration of FFAs and bfATP across all groups. (B) Relation between fasting plasma FFAs and ifATP across all groups. Patients with T2DM (n = 10) (diamonds), age- and BMI-matched controls (CONo; n = 10) (squares), and young healthy controls (CONy; n = 11) (triangles).
Figure 5
Figure 5. Glucose Metabolism and ATP Synthetic Flux during Hyperglycemic–Hyperinsulinemia in T2DM
Whole body glucose disposal (A), concentration of intramyocellular G-6-P (B), and ifATP (C) during euglycemic (approximately 5.5 mM glucose)–hyperinsulinemic (approximately 500 pM insulin) (white columns) and hyperglycemic (approximately 9.5 mM glucose)–hyperinsulinemic (approximately 500 pM insulin) clamps (hatched columns) in patients with T2DM (n = 4). * p < 0.05.
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References

    1. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: A 1H NMR spectroscopy study. Diabetologia. 1999;42:113–116. - PubMed
    1. Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, et al. Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest. 1996;97:2859–2865. - PMC - PubMed
    1. Goodpaster BH, He J, Watkins S, Kelley DE. Skeletal muscle lipid content and insulin resistance: Evidence for a paradox in endurance-trained athletes. J Clin Endocrinol Metab. 2001;86:5755–5761. - PubMed
    1. Pruchnic R, Katsiaras A, He J, Kelley DE, Winters C, et al. Exercise training increases intramyocellular lipid and oxidative capacity in older adults. Am J Physiol Endocrinol Metab. 2004;287:E857–E862. - PubMed
    1. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–387. - PubMed

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