A team of UC Davis Health scientists and physicians has identified a cellular connection between diabetes and one of its major complications – blood vessel narrowing that increases risks of several serious health conditions, including heart disease and stroke.
The authors hope their work leads to diabetes treatments – beyond blood sugar monitoring and insulin therapy – that target the molecular source of its damaging effects on the vascular system.
The same team previously found that high blood glucose, the hallmark symptom of diabetes, activates an enzyme known as protein kinase A (PKA), which increases calcium channel activity and constricts blood vessels.
“This was a surprise, since PKA is typically associated with blood vessel widening and wasn’t really on our radar,” said senior author Manuel Navedo, professor of pharmacology at UC Davis Health.
“We wanted to understand the molecular processes that created this opposite reaction.”
For the new study, published in The Journal of Clinical Investigation, the Navedo lab team conducted a series of experiments on the effects of high glucose on cerebral blood vessels and arterial cells that control blood flow.
The tests were conducted on a unique genetically modified mouse and two mouse models of diabetes that were developed at UC Davis for studies of cardiovascular health.
The researchers focused on the relationship between PKA and adenylyl cyclase (AC) – an enzyme involved in cyclic AMP (cAMP) production, a cellular messenger with a critical role in vascular cell function.
Their results showed that one AC in particular – AC5 – mediated cAMP and PKA activation, triggering increased calcium channel activity and blood vessel narrowing.
They also found that AC5 was essential for blood-vessel constriction during diabetes.
The team now hopes to test the effects of the AC5 chain reaction in high-glucose conditions in human cells.
This step could confirm it as a treatment target for reducing the vascular complications of diabetes, which can include eye, kidney, cerebral, gastrointestinal and cardiovascular disease.
“We see every day in our clinics the devastating impact of diabetes on the health and lives of our patients,” said co-author Nipavan Chiamvimonvat, the Roger Tatarian Endowed Professor in Cardiovascular Medicine at UC Davis Health.
“Our work brings into much clearer focus how high glucose can damage the vascular system and gives us a new target for blocking its effects.”
Both stroke and diabetes mellitus (DM) are increasingly common conditions that contribute to worldwide morbidity and mortality, thus necessitating urgent action.
Globally, there were 33 million estimated cases of stroke in 2013, with a loss of 39.4 and 62.8 million disability-adjusted life years (DALYs) due to ischaemic and haemorrhagic stroke, respectively.1,2
Furthermore, stroke was the second most common cause of death (11.8%) and the third most common cause of disability (4.5%).2
A systematic review of 64 studies from the Middle East indicated incidence and prevalence rates of 22.7–250 and 508–777 per 100,000 people per year, respectively.3
Over the next 20 years, stroke-related mortality is predicted to triple in Africa, the Middle East and in Latin American countries.4
In 2014, an estimated 422 million adults worldwide had DM, with the prevalence almost doubling from 4.7% in 1980 to 8.5% in 2014, the greatest burden of which was in low- and middle-income countries.5,6 In the Eastern Mediterranean region, the prevalence of DM is particularly high (3.5–30%), with Gulf Cooperation Council countries observed to have some of the highest DM prevalence rates in the region.7
Diabetes is associated with several neurological disorders, with stroke being the most well-recognised and, likely, the most common.
Diabetes is known to influence almost all varieties of stroke, including large artery stroke due to atherosclerosis, lacunar stroke and, possibly, intracerebral haemorrhage due to microvascular injury and embolic stroke due to diabetes; the latter of which is a significant risk factor for atrial fibrillation and hence part of risk factor assessment.8
Diabetic individuals have a 2.5–3.6-times higher risk of stroke compared to non-diabetics, with diabetic women at an increased risk compared to men.5,9–11 Rammal et al. estimated the prevalence of diabetes in ischaemic stroke to be 37.5% in the Arab world, based on an analysis of 29 studies of 10,242 patients.12
In an unpublished case-control study conducted in Oman, the prevalence of DM was 62.3% versus 44.7% among ischaemic stroke cases compared to controls (P <0.001).13
In another study from Oman based on stroke registry data, 52% of 600 patients with ischaemic stroke had diabetes.14
A growing body of literature in recent decades has recognised the link between DM and cerebral atrophy, as well as cognitive dysfunction.8,15–18
The strong interrelationship between DM and stroke may be due not only to micro- and macrovascular injuries associated with DM, but also to other shared risk factors such as genetic, demographic and lifestyle factors that are likely influenced by age and gender.8
In terms of the mechanism of vascular injury in diabetes, evidence indicates that hyperglycaemia (and possibly insulin resistance) leads to oxidative stress and the overproduction of reactive oxygen species, triggering multiple biochemical pathways and, ultimately, endothelial dysfunction and vascular injury.8,15
Early endothelial changes may lead to accelerated macrovascular atherosclerosis as well as changes in microvascular blood flow control and permeability.16
The phenomenon of ‘metabolic memory’ complicates the course of DM, with a prolonged progression of micro-and macrovascular complications observed, even after prompt and intensive glycaemic control.17
Currently, mechanisms of nonvascular brain injury are still being explored.
Several of the above mechanisms as well as endothelial dysfunction, alterations in blood brain barrier function and inflammation may contribute to nonvascular neurological injury.18
In view of the strong relationship between diabetes and stroke, it is natural to explore various methods of cerebrovascular evaluation to better understand the pathophysiology of these conditions or to predict episodes of cerebrovascular injury.
Carotid Doppler ultrasonography is a relatively simple and noninvasive method of visualising the superficial blood vessels and can be used to clinically evaluate the cervical carotid and parts of the vertebral arteries in the context of stroke.
Using Doppler ultrasonography, the carotid intima media thickness (CIMT) can be measured and used as surrogate evidence of vascular injury as thickening of the tunica intima is known to be a precursor of atherosclerosis.19,20
The cervical carotid arteries are a fairly easy and convenient location to study this, particularly as they are also the location of the atherosclerotic plaques that lead to stroke.
Vascular ultrasonography is another simple method of quantifying the extent of arterial narrowing, as measured by the diameter or cross-sectional area of the lumen or by recognising turbulent changes in blood flow.19,20
In this issue of SQUMJ, Nazish et al. have published a retrospective study in which they report a relationship between glycated haemoglobin (HbA1c) and CIMT and carotid plaques among adult ischaemic stroke patients who underwent carotid Doppler ultrasonography in addition to brain imaging.21
The authors found a significant association between mean HbA1c levels and increased CIMT, but not with the presence of carotid plaques.
A regression analysis indicated that dyslipidaemia and age were independently correlated with high CIMT, but not with HbA1c levels.21
The results of this study are similar to those of other studies exploring the role of carotid ultrasound CIMT and plaque findings as surrogate risk factors for stroke in general, as well as among patients with diabetes.20,22,23
However, the strength of the relationship between CIMT and stroke among diabetic patients has not yet been determined.
Increased CIMT has been associated with other factors influencing stroke, such as hypertension, hyperlipidaemia, smoking, obesity, advanced age and genetic factors.24
In addition, while some studies have demonstrated CIMT to be a risk factor for diabetes, others have demonstrated only an association on univariate analysis and not as an independent risk factor.23
Nevertheless, community-based studies of vascular changes are of value because they enhance our understanding of the underlying pathophysiological mechanisms of these conditions; in addition, such research may inform future targets of therapy or be used as markers of treatment efficacy.19,20,25
Apart from vascular ultrasonography, other methods may be of use when exploring the complex interactions between diabetes and brain dysfunction.
As mentioned earlier, diabetes is a risk factor for other mechanisms of brain injury leading to cerebral small vessel disease (CSVD), non-stroke brain atrophy and cognitive dysfunction. 18
With magnetic resonance imaging (MRI), CSVD is now recognised to comprise a spectrum of brain changes including periventricular hyperintensities, lacunar stroke, intracerebral micro- and macro-haemorrhage, enlarged perivascular spaces and cortical siderosis.26,27
Several studies have demonstrated an association between diabetic retinopathy and lacunar stroke as well as cognitive dysfunction, although the relation between CSVD and diabetic microangiopathy is not yet clear.26–28
Apart from conventional changes observed in diabetic retinopathy, such as retinal haemorrhage and changes in vascular diameter, novel methods such as optical coherence tomography, retinal vasculature fractal dimension and laser flowmetry are being explored as methods of detecting brain injury.18,29
Using video-capillaroscopy, microvasculature changes in the nail bed can be quantified and have been utilised to demonstrate a relationship with diabetic microangiopathy; this method could potentially be explored as a surrogate marker for brain injury.30
Skin autofluorescence, which reflects the accumulation of advanced glycation end-products in diabetes, has been associated with brain cortical atrophy.31
Overall, MRI is a sensitive method of studying structural changes in the brain.
A review of studies addressing MRI findings among diabetic subjects indicated that diffuse brain atrophy as well as increased CSVD changes were associated with diabetes; such changes are only explained in part by age and the presence of other adverse vascular risk factors.32
MRI is also useful in the detection of microstructural brain lesions among diabetic subjects.32,33
Attempts to link MRI findings of structural brain abnormalities to histology results may, for example, advance our understanding of the role of diabetic microvascular disease in the context of brain injury.
While such methods of studying the relation between diabetes and brain injury may help predict neurological dysfunction, a more attractive application would be to monitor novel treatments.
In conclusion, large artery stroke due to accelerated atherosclerosis is only one mechanism of neurological injury associated with diabetes, with several other mechanisms well recognised in relation to diabetes.
Cerebrovascular atherosclerosis can be easily explored using vascular Doppler ultrasonography and angiography.
However, CSVD as well as nonvascular diabetic encephalopathy are conditions that may also be explored clinically based on other methods such as retinal or skin vascular changes or utilising advanced brain MRI modalities.
More studies are necessary to explore the utility of the latter approach in predicting neurobehavioural changes in patients with diabetes, enhancing our understanding of its pathophysiology and developing better methods of managing these conditions.
More information: Arsalan U. Syed et al, Adenylyl cyclase 5–generated cAMP controls cerebral vascular reactivity during diabetic hyperglycemia, Journal of Clinical Investigation (2019). DOI: 10.1172/JCI124705
Journal information: Journal of Clinical Investigation
Provided by University of California – Davis Health
