Abstract
Aims/hypothesis
South Asians have a higher risk of developing type 2 diabetes than Europeans. The underlying cause of this excess risk is still poorly understood but might be related to differences in the regulation of energy/nutrient-sensing pathways in metabolic tissues and subsequent changes in whole-body substrate metabolism. In this study, we investigated the whole-body and skeletal muscle metabolic adaptations to short-term energy restriction in South Asian and European volunteers.
Methods
Twenty-four middle-aged overweight South Asian and European men underwent a two-step hyperinsulinaemic–euglycaemic clamp, with skeletal muscle biopsies and indirect calorimetry before and after an 8 day diet very low in energy (very low calorie diet [VLCD]). Abdominal fat distribution and hepatic triacylglycerol content were assessed using MRI and MR spectroscopy.
Results
South Asian men had higher hepatic triacylglycerol content than European men, and exhibited elevated clamp insulin levels that probably reflect a lower insulin clearance rate. Despite higher insulin levels, endogenous glucose production rate was similar and glucose disposal rate (Rd) and nonoxidative glucose disposal rate (NOGD) were significantly lower in South Asian than European men, indicating impaired whole-body insulin sensitivity. Energy restriction decreased abdominal fat mass and hepatic triacylglycerol content in both groups. However, the shift induced by energy restriction from glucose towards lipid oxidation observed in European men was impaired in South Asian men, indicating whole-body metabolic inflexibility. Remarkably, although energy restriction improved hepatic insulin sensitivity in both groups, Rd improved only in South Asian men owing to higher NOGD. At the molecular level, an increase in insulin-induced activation of the skeletal muscle mTOR pathway was found in South Asian men, showing that skeletal muscle energy/nutrient-sensing pathways were differentially affected by energy restriction.
Conclusions/interpretation
We conclude that South Asian men exhibit a different metabolic adaptation to short-term energy restriction than European men.
Trial registration: Dutch trial registry (www.trialregister.nl), trial number NTR 2473.
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Abbreviations
- 4EBP1:
-
Eukaryotic translation initiation factor 4E-binding protein 1
- ACC:
-
Acetyl-CoA carboxylase
- AMPK:
-
AMP-activated protein kinase
- AS160:
-
Akt substrate of 160 kDa
- EGP:
-
Endogenous glucose production
- ERK:
-
Extracellular signal-regulated kinase
- GS:
-
Glycogen synthase
- GSK3:
-
Glycogen synthase kinase-3
- HIR:
-
Hepatic insulin resistance
- IQR:
-
Interquartile range
- IRβ:
-
Insulin receptor β
- IRS1:
-
Insulin receptor substrate 1
- LBM:
-
Lean body mass
- MCRi :
-
Metabolic clearance rate of insulin
- mtDNA:
-
Mitochondrial DNA
- mTOR:
-
Mammalian target of rapamycin
- mTORC1:
-
Mammalian target of rapamycin complex 1
- nDNA:
-
Nuclear DNA
- NEFA:
-
Nonesterified fatty acid
- NOGD:
-
Nonoxidative glucose disposal
- PKB:
-
Protein kinase B
- PPARα:
-
Peroxisome proliferator-activated receptor α
- PRAS40:
-
Proline-rich Akt substrate of 40 kDa
- Rd :
-
Rate of glucose disposal
- REE:
-
Resting energy expenditure
- RQ:
-
Respiratory quotient
- S6K1:
-
Ribosomal protein S6 kinase β1
- TSC2:
-
Tuberous sclerosis complex 2
- VLCD:
-
Very low calorie diet
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Acknowledgements
We are greatly indebted to E. J. M. Ladan-Eygenraam (Leiden University Medical Centre, Leiden, the Netherlands) for her technical assistance during the study.
Funding
We thank Roba Metals B. V. IJsselstein (Utrecht, the Netherlands) for financial support. Funding by the Netherlands Heart Foundation (Project UL 2009-4548) is gratefully acknowledged (The Hague, the Netherlands). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Contribution statement
All authors have read and approved the final version of the manuscript, and meet all three conditions as stated by the International Committee of Medical Journal Editors uniform requirements for manuscripts submitted to medical journals. LEHB contributed to the acquisition, analysis and interpretation of all data and drafted the manuscript. BG contributed to the acquisition, analysis and interpretation of skeletal muscle data and reviewed the manuscript. LDS contributed to the acquisition, analysis and interpretation of MR data and reviewed the manuscript. GCMZ contributed to the acquisition of skeletal muscle data and reviewed the manuscript. TCMS contributed to the acquisition of clamp data and reviewed the manuscript. JBK provided the statistical model, contributed to the analysis of data and reviewed the manuscript. JTJ contributed to the design of the MR protocol, contributed to the acquisition and interpretation of MR data and reviewed the manuscript. HJL contributed to the analysis and interpretation of MR data and reviewed the manuscript. JWAS contributed to the conception and design of the MR protocol, contributed to the analysis and interpretation of data and reviewed the manuscript. HP contributed to the analysis and interpretation of data and reviewed the manuscript. AEM contributed to the conception and design of the study protocol, contributed to the analysis and interpretation of all data and reviewed the manuscript. IMJ contributed to the conception and design of the protocol, contributed to the acquisition, analysis and interpretation of all data and reviewed the manuscript.
LEHB and IMJ are the guarantors of this work and, as such, have full access to all the data generated in the framework of the study and take responsibility for their integrity and the accuracy of their analysis.
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Bakker, L.E.H., Guigas, B., van Schinkel, L.D. et al. Middle-aged overweight South Asian men exhibit a different metabolic adaptation to short-term energy restriction compared with Europeans. Diabetologia 58, 165–177 (2015). https://doi.org/10.1007/s00125-014-3408-4
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DOI: https://doi.org/10.1007/s00125-014-3408-4