Time Restricted Eating Improves Intermittent Hypoxia-Induced Dysglycemia

Abstract

Study objectives: Obstructive sleep apnea (OSA) is associated with maladaptive changes to glucose homeostasis. Chronic intermittent hypoxia (IH) modeling OSA in rodents causes similar patterns of dysglycemia. Time restricted eating (TRE), limiting caloric intake to a fixed daily window, improves the metabolic profile in rodents and humans, though it is unknown whether TRE improves IH-induced dysglycemia in an obese OSA model.

Methods: C57BL/6J mice were fed a high-fat diet (HFD) for four weeks, and then divided into four groups: Half in intermittent air (IA) or IH, and half from each group fed either ad libitum or by TRE, restricting HFD intake to 9h/d during the dark phase; exposures continued for four additional weeks. Glucose tolerance tests (GTT) were performed before and after exposures.

Results: Fasting glucose was reduced in IH-TRE (-25.4±5.6 mg/dL, p<0.001) but not in other groups. GTT area under the curve was only increased in the IA-ad lib (3155±924 mg*min/dL, p=0.002) and IH-ad lib groups (5267±1161 mg*min/dL, p<0.001), but TRE prevented these increases. Insulin was elevated in IA-ad lib relative to other groups (p<0.010 for all), implying insufficient insulin response to hyperglycemia in IH-ad lib. Serum proinsulin, and the proinsulin to insulin ratio, were elevated in IH-ad lib mice; this was normalized with TRE, along with favorable changes to pancreatic glucokinase, prohormone convertase 1/3, and miR-152-3p.

Conclusions: In IH, TRE mitigates adverse hypoxic effects on glucose homeostasis, via improvements in pancreatic insulin secretion. Some beneficial glycemic effects of TRE are accentuated in IH. TRE may represent a novel therapeutic strategy in OSA.

Keywords: Metabolic syndrome; hypoxia; intermittent fasting; proinsulin; sleep disordered breathing.