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. 2013 Jan;36(1):91-101.
doi: 10.1007/s10545-012-9486-x. Epub 2012 May 12.

Substrate metabolism during basal and hyperinsulinemic conditions in adolescents and young-adults with Barth syndrome

W Todd Cade  1 , Carolyn T Spencer, Dominic N Reeds, Alan D Waggoner, Robert O'Connor, Melissa Maisenbacher, Jan R Crowley, Barry J Byrne, Linda R Peterson
Affiliations

Substrate metabolism during basal and hyperinsulinemic conditions in adolescents and young-adults with Barth syndrome

W Todd Cade et al. J Inherit Metab Dis. 2013 Jan.

Abstract

Background: Barth syndrome (BTHS) is a rare X-linked disorder that is characterized by mitochondrial abnormalities, infantile or childhood onset of cardioskeletal myopathy, and high mortality rates. It is currently unknown if BTHS related mitochondrial dysfunction results in substrate metabolism abnormalities and thereby contributes to cardioskeletal myopathy in patients with BTHS.

Methods: Adolescents and young adults with BTHS (n = 5, 20 ± 4 yrs) and age and activity matched healthy controls (n = 5, 18 ± 4 yrs) underwent an hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracers for measurement of lipolysis, fatty acid oxidation, glucose disposal, and whole-body proteolysis rates; dual energy x-ray absorptiometry for measurement of body composition and 2-D and strain echocardiography for measurement of left ventricular function.

Results: Participants with BTHS had lower fat-free mass (FFM) (BTHS: 31.4 ± 6.9 vs.

Control: 46.7 ± 5.3 kg, p < 0.005), lower systolic function (strain, BTHS: -15.2 ± 2.4 vs.

Control: -19.0 ± 2.4 %, p < 0.05), greater insulin-stimulated glucose disposal rate per kg FFM (BTHS: 96.5 ± 16.3 vs.

Control: 67.4 ± 17.6 μmol/kgFFM/min, p < 0.05), lower basal (BTHS: 4.6 ± 2.7 vs.

Control: 11.9 ± 4.4 μmol/kgFM/min, p < 0.05) and hyperinsulinemic (BTHS: 1.6 ± 0.4 vs.

Control: 3.6 ± 1.6 μmol/kgFM/min, p < 0.05) lipolytic rate per kg fat mass (FM), and a trend towards higher basal leucine rate of appearance per kg FFM (BTHS: 271.4 ± 69.3 vs.

Control: 193.1 ± 28.7 μmol/kgFFM/hr, p = 0.07) compared to controls. Higher basal leucine rate of appearance per kg FFM (i.e. whole-body proteolytic rate) tended to be associated with lower left ventricular systolic strain (r = -0.57, p = 0.09).

Conclusion: Whole-body fatty acid, glucose and amino acid metabolism kinetics when expressed per unit of body composition are altered and appear to be related to cardioskeletal myopathy in humans with BTHS. Further studies examining myocardial substrate metabolism and whole-body substrate metabolism during increased energy demands (e.g., exercise) and their relationships to skeletal and cardiac function are recommended.

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Figures

Figure 1
Figure 1
Glucose rate of disappearance in BTHS and controls during the basal and hyperinsulinemic condition. BTHS: Barth syndrome, Rd: rate of disappearance, HyperIns: hyperinsulinemia, FFM: fat free mass. *: p<0.05
Figure 2
Figure 2
Palmitate rate of appearance in BTHS and controls during the basal and hyperinsulinemic condition. BTHS: Barth syndrome, Ra: rate of appearance, HyperIns: hyperinsulinemia, FM: fat mass. *: p<0.05
Figure 3
Figure 3
Leucine rate of appearance in BTHS and controls during the basal and hyperinsulinemic condition. BTHS: Barth syndrome, Ra: rate of appearance, HyperIns: hyperinsulinemia, FFM: fat free mass. *: p=0.09
Figure 4
Figure 4
Plasma Amino Acid Levels in BTHS and Control Participants. Phe: phenylalanine, Tyr: tyrosine, Ile: isoleucine, Leu: leucine, Val: valine, Thr: Threonine, Ser: serine, Gly: Glycine, Met: methionine, Cys: cysteine, Gln: glutamine, Glu: glutamate, Arg: arginine, Ala: alanine, Pro: proline, Lys: lysine, His: histidine, Cit: citrulline, Ort: ornithine. *: p<0.05.
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