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Role of Oxygen Insufficiency in the Onset & 259
Development of Vascular Complications of Diabetes

thelium-derived hyperpolarization factor (EDHF), ni- ISCHEMIC PRECONDITIONING
tric oxide (NO) and prostacyclin (PGI ),serve to dilate Ischemic preconditioning (IPC) or postconditioning
2
the vessel and confer anti-proliferative effects. While (Ipost) is proved to efficiently prevent ischemia/
endothelin-1 (ET-1), angiotensin II and reactive oxygen reperfusion injuries. Mortality of diabetic patients
species (ROS) are those that exert vasoconstrictor ef- with acute myocardial infarction was found to be 2–6
fects. Endothelial cells also produce antithrombotic folds higher than that of non-diabetic patients with
(NO and PGI both inhibit platelet aggregation) and same myocardial infarction, which may be in part due
2
prothrombotic molecules [von Willebrand factor, to diabetic inhibition of IPC- and Ipost-mediated pro-
which promotes platelet aggregation, and plasmin- tective mechanisms . It been demonstrated that dia-
8,9
ogen activator inhibitor-1 (PAI-1), which inhibits fibri- betes may alter both sarcolemmal and mitochondrial
nolysis] .
4
K-ATP channels and then alter mitochondrial func-
10
Endothelial dysfunction causes shift in vasculature tion . The oxidative stress due the altered availabity
toward reduced vasodilation, a proinflammatory of redox enzymes aggravates cellular injury.
state, and prothrombic state. Free radicals can dis-
rupt the balance of NO, damaging the endothelium, CLINICAL IMPLICATIONS
aggravating the dysfunction and promoting athero- Retinopathy onset and progress is by high oxidative
sclerosis. Thus setting off a vicious cycle,with wors- stress and hyperglycemia induced pseudohypoxia ,
ening imbalance, resulting in widespread disease . triggering a casdae of activity causing leaking of the
5
blood vessels, recruitment of VEGF, causing prolifer-
CHANGES IN HYPOXIA INDUCIBLE ation of new blood vessels, which are prone to hae-
FACTOR morrhage due to their fragility.
Hypoxia-inducible factor-1 (HIF-1) is responsible for Early stages of nephropathy, characterized by hyper-
activating the genes encoding glucose transporters, filtaration increases the load on SGLT channels and
11
glycolytic enzymes, mitochondrial enzymes that make causes increased oxygen consumption in addition
metabolism more efficient under hypoxic conditions to prevalence of the other factors discussed earlier,
.It controls various phenomena including growth, sur- causing chronic tubulointerstitial injury progressing
vival, angiogenesis, glucose metabolism.There is evi- to ESRD.
dence to suggest that a high osmotic stress inhibits
HIF transcription Excessive Reactive Oxygen Species Endoneural Hypoxia as a result of reduction in nerve
present in hyperglycemic states induces a conforma- blood flow and increased endoneural vascular resi-
tional change in the P300 component of HIF-1 due tance causes progressive diabetic polyneuropathy.
to the glycolytic metabolite methyglyoxal. P300 is a Micro vascular diseases accelarates atherosclerosis,
functional component attached to HIF-1-beta. This through processes we have just reviewed. Combined
conformational change results in modification of the with the lose of Ischemic preconditioning, the impact
5,6
transcriptional property of HIF-1 . of hyperglycemia and hyperlipidemia causes a sig-
nificantly higher mortality and morbidity in diabetic
individuals.
Thus, control of hyperglycemia appears to be the
sheet anchor on which our efforts to reduce the com-
plications of diabetes rest upon.

REFERENCES
Hypoxia, at least in part through activation of the 1. Fowler MJ. Microvascular and macrovascular complications of diabetes.
hypoxia inducible factor 1 (HIF-1) α-related pathways, Clinical Diabetes 2008;26(2):77-82.Chawla A, Chawla R, Jaggi S. Micro-
controls all steps of the postischemic revasculariza- vasular and macrovascular complications in diabetes mellitus: Distinct or
tion process. Recent studies uncover that destabiliza- continuum? Indian J EndocrinolMetab 2016;20(4):546-51.
tion of HIF-1 is most likely the event that transduces 2. Kitada M, Zhang Z, Mima A, King GL. Molecular mechanisms of diabetic
hyperglycemia into the loss of the cellular response vascular complications. J Diabetes Investig 2010;1(3):77-89.
to hypoxia in most diabetic complications. Downreg- 3. Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms
ulation of HIF-1 in response to hyperglycemia also of injury and protective factors. Cell Metab 2013;17(1):20-33.
seems to account for the decreased collateral growth 4. Schmid T, Zhou J, Köhl R, Brüne B. p300 relieves p53-evoked transcription-
triggered by myocardial ischemia in patients with di- al repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 2004;380(Pt
abetes . 1):289-95.
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