Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic β‐cell replication in mice

Abstract

Obstructive sleep apnoea (OSA) and type 2 diabetes frequently co-exist and potentially interact haemodynamically and metabolically. However, the confounding effects of obesity have obscured the examination of any independent or interactive effects of the hypoxic stress of OSA and the hyperglycaemia of type 2 diabetes on haemodynamic and metabolic outcomes. We have developed a chronically catheterized, unhandled, lean murine model to examine the effects of intermittent hypoxic (IH) exposure and exogenous glucose infusion on the diurnal pattern of arterial blood pressure and blood glucose, as well as pancreatic β-cell growth and function. Four experimental groups of adult male C57BL/J mice were exposed to 80 h of (1) either IH (nadir of inspired oxygen 5-6% at 60 cycles h −1 for 12 h during light period) or intermittent air (IA; control) and (2) continuous infusion of either 50% dextrose or saline (control). IH exposure during saline infusion caused a sustained increase in arterial blood pressure of 10 mmHg (P < 0.0001), reversed the normal diurnal rhythm of blood glucose (P < 0.03), doubled corticosterone levels (P < 0.0001), and increased replication of pancreatic β-cells from 1.5 ± 0.3 to 4.0 ± 0.8% bromodeoxyuridine (BrdU)-positive) β-cells. The combined stimulus of IH exposure and glucose infusion attenuated the hypertension, exacerbated the reversed diurnal glucose rhythm, and produced the highest rates of apoptosis in β-cells, without any additive effects on β-cell replication. We conclude that, in contrast to the development of sustained hypertension, IH impaired glucose homeostasis only during periods of hypoxic exposure. IH acted as a stimulus to pancreatic β-cell replication, but the presence of hyperglycaemia may increase the hypoxic susceptibility of β-cells. This model will provide a basis for future mechanistic studies as well as assessing the metabolic impact of common comorbities in OSA, including obesity, insulin resistance and type 2 diabetes.

Intermittent Hypoxia in Pancreatic beta Cells

“…These results indicate that IH directly increases β cell proliferation [18]. The results were well fitted the results that pancreatic β cell proliferation in vivo mouse model of intermittent hypoxia [15]. …”

“…On the other hand, hyperglycemia is known to increase the rate of β cell replication [13,14], which can provide an increased source of insulin to combat insulin resistance. In a mouse model, IH was found to cause β cell replication without hyperglycemia [15,16], suggesting a possible mechanism that IH directly stimulates β cell replication. Here, we focus on the impact of IH on pancreatic β cells, particularly β cell dysfunction and proliferation, using an in vitro IH system [17,18].…”

Sleep apnoea and metabolic dysfunction

“…and increased oxidative stress [13]. Such intermittent hypoxia-related intermediate mechanisms are known to alter insulin signalling, as was directly demonstrated by some cultured cell and murine studies [14,15].…”

Sleep, sleep-disordered breathing and metabolic consequences

“…The magnitude of metabolic alterations may also depend on the severity of IH [184]. However, in contrast to the persistent effects of chronic IH on sympathetic activity and blood pressure, the effects of IH on glucose homeostasis appear to be limited to the periods of hypoxic exposure [187]. Moreover, combining IH exposure and glucose infusion amplified the alteration of blood glucose diurnal rhythm and led to high rates of apoptosis in b-cells [187].…”