f56d29ddbbd7d540d1db186a089c9fe59484
f56d29ddbbd7d540d1db186a089c9fe59484
f56d29ddbbd7d540d1db186a089c9fe59484
DOI: https://doi.org/10.17925/USE.2017.13.01.17
H
yperglycemia is due to a dysregulation in the complex mechanisms implicated in glucose homeostasis. Chronic hyperglycemia, as
measured by hemoglobin A1c (HbA1c), is a key risk factor for the development of microvascular and macrovascular complications,
which in turn negatively influence the prognosis of patients with diabetes. Several studies have shown that acute hyperglycemia can
add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can manifest as high fasting plasma glucose (FPG) or
high postprandial plasma glucose (PPG) and can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. Glucose
variability, as expressed by the intraday glucose fluctuations from peaks to nadirs, is another important parameter, which has emerged as an
HbA1c-independent risk factor for the development of vascular complications, mainly in the context of type 2 diabetes. Treatments able to
decrease HbA1c have been associated with positive effects in terms of reducing risk for the development and progression of complications.
Further studies are required to clarify the impact of strategies more specifically targeting components of acute hyperglycemia, to improve
outcomes in patients with diabetes.
The combined alterations in insulin and glucagon production/secretion in diabetes is the reason
why recently there has been increasing interest in developing new therapeutic strategies to achieve
normoglycemia based on a bihormonal approach, delivering insulin and glucagon simultaneously.5
In addition, the ongoing advances in the understanding of the complex hormonal regulation of
glucose metabolism have also led to the development of new drugs to be implemented to treat
hyperglycemia, such as GLP-1 or amylin analogs.3
2 US E ND OCRINOLOG Y
Complications of Acute and Chronic Hyperglycemia
healthcare providers to raise awareness. In addition, preventive strategies Figure 1: Different components of hyperglycemia in relation
should be applied to avoid episodes of DKA in patients with an already to complication risk
known diagnosis of diabetes. This requires patient education and access to
specific diabetes programs and services.
Hyperglycemia
Diabetic peripheral neuropathy is a common complication estimated to AGEs have been implicated in several biologic activities, mostly by binding
affect 30–50% of individuals with diabetes, although clinical symptoms do to the AGE-specific receptors (RAGEs) on many cells. In particular, they can
not generally occur until long after the onset of diabetes. Abnormalities of induce oxidative stress and release of cytokines and growth factors, which
the autonomic nervous system can also occur in patients with diabetes, in turn accelerate chronic inflammation and endothelial dysfunction.28
with early subclinical manifestations, such as decreased heart rate
variability, being detectable within a year of diagnosis in patients with T2D, Growing evidence suggests that increased oxidative stress, induced
and within two years in patients with T1D.37 by the above hyperglycemia-activated pathways, is a key factor in the
pathogenesis of endothelial dysfunction and vascular disease. Several
With regard to macrovascular complications, epidemiologic data indicate mitochondrial and other intracellular pathways are implicated in the
that people with diabetes have a two- to fourfold increased risk of developing increased production of oxidant species concomitant with a reduction in
cardiovascular disease, which in turn is a key contributor of mortality.38 antioxidants in the context of diabetes.28,39
US E NDO CRIN O L OG Y 3
Review Diabetes
In addition to the above pathways/mechanisms, recent studies have also blood glucose levels over a 2- to 3-month period, with plasma glucose
suggested the involvement of hyperglycemia-induced epigenetic changes levels in the preceding 30 days contributing 50% to the final result, and
and microRNA levels in the pathogenesis of diabetes vascular complications.40 plasma glucose levels from 90–120 days earlier contributing only 10%.50
The DCCT/EDIC, UKPDS, and several other studies have clearly shown
Intervention to improve glycemic control the strong association between HbA1c and vascular complications of
The Diabetes Control and Complications Trial (DCCT) and its follow-up study, diabetes.41,48,51 During recent years, the effect of long-term glucose variability,
the Epidemiology of Diabetes Interventions and Complications (EDIC), have as assessed by the intraindividual variability of HbA1c values across visits,
clearly shown the role of strict glycemic control in reducing the risk of on retinopathy, nephropathy, and cardiovascular complications has also
vascular complications in subjects with T1D.40–42 been documented.52
The DCCT studied a cohort of 1,441 subjects, aged 13–39 years, with T1D for However, HbA1c measurement does not give any information about
1–15 years42 by comparing intensive (insulin administered three or more times individual daily glucose fluctuations (short-term fluctuations or acute
daily by injection or an external pump) versus conventional (one or two daily hyperglycemia). In patients with marked fluctuations in glucose
insulin injections) insulin therapy. Intensive insulin therapy reduced the risk for concentrations who are exposed to the risk of both hyperglycemia and
the development of retinopathy by 76%, slowed retinopathy progression by hypoglycemia, HbA1c levels may still indicate adequate metabolic control.53
54%, and reduced the development of proliferative or severe nonproliferative
retinopathy by 47%. Intensive insulin therapy reduced the occurrence of Extensive evidence indicates that short-term fluctuations in glucose
diabetic nephropathy by 39–54% and that of clinical neuropathy by 60%. In (acute hyperglycemia) can play a key role in the pathogenesis of diabetic
the DCCT intensive treatment also reduced the risk of any cardiovascular vascular complications, independently from the effect on HbA1c.53
disease event by 42% and the risk of nonfatal myocardial infarction, stroke, Acute hyperglycemia can be due to high FPG and/or high PPG levels.
or death from cardiovascular disease by 57%.42 Although already after 2 The contribution of FPG and PPG to long-term glycemic control varies
years from the end of the DCCT, HbA1c levels were similar between the across the range of HbA1c concentrations. In particular, it has been shown
previously intensively and conventionally treated groups, complication rates that, whereas the relative contribution of PPG decreases from the lowest
in the previously intensive treated group were still lower, thus postulating the to the highest quintiles of HbA1c, the relative contribution of FPG increases
concept of the “metabolic memory.”43 That is, patients who were previously with higher levels of HbA1c.53
exposed to better glycemic levels continued to have an advantage in terms
of protection from the development of chronic complications several years Acute hyperglycemia has been associated with increased renal perfusion,
later. Therefore, the EDIC study highlighted the need of implementing intensive hyperfiltration, increased oxidative stress, decreased motor and sensory
management as soon as diabetes is diagnosed. This was further confirmed by nerve conduction, increased collagen production in the kidney, and
more recent EDIC data showing significant differences in the persistence of increased retinal perfusion. All these mechanisms can contribute to the
the “metabolic memory” between the DCCT adolescent and adult cohorts.44 development of microvascular complications.53 In addition, short glucose
At year 10 of EDIC the advantage of the previous intensively insulin treatment excursions can induce endothelial dysfunction, increase oxidative stress,
in terms of diabetic retinopathy progression still persisted in the adult cohort, activate coagulation factors, increase the expression of adhesion molecules,
whereas it did not in the adolescent cohort. These contrasting findings increase blood pressure, and dyslipidemia. Again, all these mechanisms
between adults and adolescents were largely explained by the difference can contribute to the development of macrovascular complications.53
in HbA1c during the DCCT years, when, within the intensively treated group,
adolescents consistently showed a mean HbA1c 1% higher than adults.44 Although there is some increasing evidence for a role of acute
hyperglycemia, such as PPG, in the development of vascular complications,
The mechanisms underpinning this “metabolic memory” remain unclear. there is still a need of further data, mainly obtained from interventional
However, recent data suggest that epigenetic modulations, such as studies exploring drugs specifically targeting PPG.
histones and DNA methylation, may be involved in persistent changes of
gene expression associated with vascular complications of diabetes and Short-term glucose variability, which represents the intraday glucose
lead to metabolic memory.45,46 Of interest, a recent study demonstrated fluctuations from peaks to nadirs, is another parameter, reflecting
that specific microRNA (i.e., miR-125b and miR-146a-5) changes can cause short-glucose fluctuations and which has been investigated in relation to
persistent increase in proatherogenic gene expression and explain in this diabetic vascular complications.54
way the phenomenon of metabolic memory.47
In vitro studies have shown a significant effect of glucose fluctuations
The key role of glycemic control in modulating complication risks in the activation of oxidative stress pathways, induction of epigenetic
highlighted by the DCCT/EDIC studies was also confirmed by large studies changes in key genes, and endothelial dysfunction. Several studies
performed in adults with T2D, such as the UKPDS, where for example performed in patients with T2D have shown a direct association between
intensive treatment (insulin or sulfonylurea) resulted in a 25% decrease in glucose variability and the development or progression of retinopathy,
microvascular complications.48 cardiovascular disease and mortality.55,56 In contrast, some studies in
patients with T1D have shown that glucose variability has a small effect
Chronic versus acute hyperglycemia in the on the development of diabetic complications, with few studies reporting
pathogenesis of vascular complications an association with microvascular complications, whereas it appears that
Hemoglobin A1C (HbA1c) is the main parameter which has been used for there is no link with macrovascular disease.55,56 Data from the DCCT showed
over 30 years to monitor long-term glycemic control.49 HbA1c levels reflect no association between measures of glucose variability and microvascular
4 US E ND OCRINOLOG Y
Complications of Acute and Chronic Hyperglycemia
complications.57 Similarly, another study in patients with T1D could not development of both micro- and macrovascular complications of diabetes.
confirm the association found in patients with T2D between oxidative stress In addition, there is growing evidence suggesting that acute hyperglycemia,
and glucose variability.55 Further studies are required to clarify the role particularly PPG, plays a role in the pathogenesis of complications.
of glucose variability as a potential additional component in the network of In contrast, the role of glucose variability in the development of vascular
vascular complications of diabetes. complications is not yet clear.
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