Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 552, Issue 1, Pages 253-264Publisher
WILEY
DOI: 10.1113/jphysiol.2003.048173
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Funding
- NHLBI NIH HHS [F32 HL 71469, R01 HL 71506, R01 HL 37379, R01 HL063767, K08 HL068715, K23 HL 04065, R01 HL037379, R01 HL 63767, R01 HL071506, F32 HL071469, K08 HL 68715, R01 HL 66324] Funding Source: Medline
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Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lep(ob)) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl(-1) on day 0 to 138 +/- 10 mg dl(-1) on day 5, P < 0.01), improvement in glucose tolerance without a change in serum insulin levels and an increase in serum leptin levels in comparison with control (2.6 +/- 0.3 vs. 1.7 +/- 0.2 ng ml(-1), P < 0.05). Microarray mRNA analysis of adipose tissue revealed that leptin was the only upregulated gene affecting glucose uptake. In obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136% (P < 0.01) increase in serum insulin levels. This increase in insulin secretion after 5 days of intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml(-1) at baseline to 9.8 +/- 1.8 ng ml(-1) at week 12, P < 0.001) and worsening glucose tolerance, consistent with an increase in insulin resistance. We conclude that the increase in insulin resistance in response to intermittent hypoxia is dependent on the disruption of leptin pathways.
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