Reduced basal ATP synthetic flux of skeletal muscle in patients with previous acromegaly

Abstract

Background: Impaired mitochondrial function and ectopic lipid deposition in skeletal muscle and liver have been linked to decreased insulin sensitivity. As growth hormone (GH) excess can reduce insulin sensitivity, we examined the impact of previous acromegaly (AM) on glucose metabolism, lipid storage and muscular ATP turnover.

Participants and methods: Seven AM (4f/3 m, age: 46+/-4 years, BMI: 28+/-1 kg/m(2)) and healthy volunteers (CON: 3f/4 m, 43+/-4 years, 26+/-2 kg/m(2)) matched for age and body mass underwent oral glucose testing for assessment of insulin sensitivity (OGIS) and ss-cell function (adaptation index, ADAP). Whole body oxidative capacity was measured with indirect calorimetry and spiroergometry. Unidirectional ATP synthetic flux (fATP) was assessed from (31)P magnetic resonance spectroscopy (MRS) of calf muscle. Lipid contents of tibialis anterior (IMCLt) and soleus muscles (IMCLs) and liver (HCL) were measured with (1)H MRS.

Results: Despite comparable GH, insulin-like growth factor-1 (IGF-I) and insulin sensitivity, AM had approximately 85% lower ADAP (p<0.01) and approximately 21% reduced VO(2)max (p<0.05). fATP was similarly approximately 25% lower in AM (p<0.05) and related positively to ADAP (r = 0.744, p<0.01), but negatively to BMI (r = -0.582, p<0.05). AM had approximately 3 fold higher HCL (p<0.05) while IMCLt and IMCLs did not differ between the groups.

Conclusions: Humans with a history of acromegaly exhibit reduced insulin secretion, muscular ATP synthesis and oxidative capacity but elevated liver fat content. This suggests that alterations in ss-cell function and myocellular ATP production may persist despite normalization of GH secretion after successful treatment of acromegaly.

Figure 1. Whole-body insulin sensitivity, maximal oxygen consumption and muscle mitochondrial ATP production (means±SEM): (A) OGIS (B) VO₂max (p<0.05) and (C) flux through ATP synthesis (fATP) (p<0.05) in 7 subjects with previous acromegaly (AM, full bars) and 7 age- and body mass index-matched controls (CON, empty bars).

Figure 2. Ectopic lipid deposition: (A) in M.soleus (IMCLs), (B) M.tibialis ant. (IMCLt) and (C) in the liver (HCL) (p<0.05).

Figure 3. Relationship between ectopic lipid content of tibialis muscle (IMCLt) and plasma concentrations of insulin-like growth factor-1 (IGF-I) in 7 subjects with previous acromegaly (AM, black squares) and 7 age- and body mass index-matched controls (CON, grey squares) (r = 0.726, p<0.05).