Studies on the Adaptive Responses (Cardiovascular, Respiratory and Angiogenetic) to Hypoxia in Patients With Type 1 Diabetes Compared to Controls

Complications of diabetes represent the main concern for modern diabetes therapy, and it has become a priority to further characterise the pathophysiological mechanisms of these complications to ensure the development of novel rational therapeutic strategies.

Although the prolonged exposure of tissues to hyperglycaemia is the primary causative factor for chronic diabetes complications, it has recently become increasingly evident that hypoxia also plays an important role in all diabetes complications . A low tissue concentration of oxygen in diabetes is the consequence of several mechanisms (e.g., deficient blood supply because of micro- and macro-vascular disease , poor local oxygen diffusion because of local oedema, or as the result of increased oxygen consumption).

Adaptive responses of cells to hypoxia are mediated by Hypoxia-Inducible Factor 1 (HIF), which is a heterodimeric transcription factor that is composed of and subunits, which are both constitutively expressed in mammalian cells. The regulation of HIF activity is critically dependent on subunit degradation in normoxia. Under hypoxic conditions, HIF-1 is stabilised, binds to HRE (hypoxic responsive elements) and up-regulates a gene series that is involved in angiogenesis, glycolytic energy metabolism, cell proliferation, and survival, which enables cells to adapt to reduced oxygen availability. It is estimated that that more than 800 genes are direct HIF targets . HIF-1 is central for expression of multiple angiogenic growth factors (reviewed by[6]), endothelial progenitor cells (EPC) recruitment . Recently, it has been proposed that microRNAs (ex. mir210) also mediate some HIF-1 functions .

Several pieces of evidence point to a defective response of diabetic tissues to hypoxia. An impaired hypoxia response is present in all tissues investigated in diabetic animal and diabetic patients. Hyperglycaemia directly represses HIF stability and function at multiple levels, a mechanism that is not completely understood.

An impaired reaction to hypoxia in diabetes might have important consequences in acute hypoxic challenges as acute heart infarction, stroke, limb ischemia but also in subtle regulation of cardiovascular and respiratory system as a consequence of autonomic neuropathy with potential severe prognostic effect on late cardiovascular events . Interventional studies have addressed the cardiovascular responses to intermittent hypoxia (IH) compared with normoxia exposure in patients with diabetes . However in order to establish the appropriateness of the cardiovascular reaction to hypoxia in diabetes it is a need to investigate the cardiorespiratory responses towards IH in patients with diabetes compared with matched non diabetic control subjects. Moreover it is essentially to establish the angiogenetic response in the same experimental design. The hypothesis for this study is that both the cardiorespiratory reaction mediated through autonomic nervous system and angiogenetic response are impaired in patients with diabetes as a consequence of an impaired HIF reaction as seen in other tissues .