Location via proxy:   [ UP ]  
[Report a bug]   [Manage cookies]                

f56d29ddbbd7d540d1db186a089c9fe59484

Download as pdf or txt
Download as pdf or txt
You are on page 1of 5

Review Diabetes

Complications of Acute and Chronic


Hyperglycemia
M Loredana Marcovecchio
University of Cambridge, Cambridge, UK

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.

Keywords From glucose homeostasis to hyperglycemia


Hyperglycemia, complications, Glucose homeostasis is maintained by a complex neurohormonal system, which modulates
vascular, acute, chronic peripheral glucose uptake, hepatic glucose production, and exogenous glucose utilization following
food ingestion.1,2 This allows the maintenance of plasma glucose concentrations within normal range,
Disclosure: M Loredana Marcovecchio has nothing to
disclose in relation to this article. No funding was received with average values of around 90 mg/dl throughout a 24-hour period, postmeal concentration below
in the publication of this article. This study involves a review 140 mg/dl, and minimal values, such as those after moderate fasting or exercise, above 55 mg/dl.1,2
of the literature and did not involve any studies with human
or animal subjects performed by any of the authors.
Authorship: Thel named author meets the International Hormones implicated in glucose regulation include insulin, glucagon, amylin, glucagon-like petide-1
Committee of Medical Journal Editors (ICMJE) criteria (GLP-1), glucose-dependent insulinotropic peptide, epinephrine, cortisol, and growth hormone.3
for authorship of this manuscript, takes responsibility
for the integrity of the work as a whole, and has given These hormones act on several target tissues, including muscle, liver, adipocyte, and brain to regulate
final approval to the version to be published. glucose levels.3
Open Access: This article is published under the
Creative Commons Attribution Noncommercial License,
which permits any non-commercial use, distribution, Insulin is a key glucoregulatory hormone, produced by pancreatic β-cells, whose levels are low during
adaptation and reproduction provided the original the fasting state, whereas they increase during the postprandial phase, when insulin stimulates
author(s) and source are given appropriate credit.
utilization of dietary glucose by peripheral tissues, and in the meantime represses hepatic glucose
Received: February 27, 2017
Accepted: March 30, 2017
production.4 Another important hormone regulating glucose metabolism is glucagon, produced by
Citation: US Endocrinology, pancreatic α-cells during fasting conditions, when it induces hepatic glucose production through the
2017;13(1):Epub ahead of printx activation of glycogenolysis and, with more prolonged fasting, also stimulation of gluconeogenesis.5
Corresponding Author: M Loredana Marcovecchio,
University of Cambridge, Box 116, Level 8, Cambridge
Biomedical Campus, Hills Road, Cambridge, CB2 A dysregulation in the mechanisms implicated in glucose homeostasis can cause acute or chronic
0QQ, UK. E: mlm45@medschl.cam.ac.uk hyperglycemia.6 Decreased/assent insulin production and/or reduced insulin sensitivity are important
contributing factors to the development of hyperglycemia and they represent the underlying
abnormalities of diabetes.4 Along with a decreased/absent insulin secretion, diabetes is also
characterized by impaired glucagon production, which can predispose to the risk of hypoglycemia in
these patients.5 However, there is also extensive evidence that in patients with diabetes, hyperglycemia
is often associated with hyperglucagonemia.5

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

TOUC H MED ICA L MEDIA 1


Review Diabetes

The spectrum of hyperglycemia Complications of hyperglycemia


Diabetes High glucose concentrations can cause injury to a large number of
Chronic hyperglycemia is the hallmark of diabetes mellitus, a chronic organs and tissues.6 Most cells can adapt the rate of intracellular glucose
condition characterized not only by hyperglycemia but also by transport under hyperglycemia conditions, and they can protect the
alterations in protein and lipid metabolism.7 The definition of diabetes intracellular milieu from the negative effect of high glucose levels. In
is based on fasting glucose levels ≥126 mg/dl or random glucose levels contrast, other cells, such as β cells, neuronal, and endothelial cells,
≥200 mg/dl.7 are unable to activate this control of glucose afflux and they equilibrate
their intracellular glucose level to the extracellular concentrations, and
Among the various forms of diabetes, type 1 diabetes (T1D) is characterized therefore are more susceptible to the effect of hyperglycemia.1,2,28
by an autoimmune destruction of pancreatic β-cells, and is the most
frequent form in the pediatric population, representing more than 90% of In the context of diabetes, hyperglycemia can cause acute and chronic
all cases of diabetes diagnosed during childhood and adolescence.7 Over complications, which represent important determinants of morbidity and
the last decades there has been a progressive increase in the incidence mortality, and have a negative impact on the prognosis of people affected
of T1D in children and adolescents.8 Based on recent data from the by this disease.29
International Diabetes Federation, worldwide there are around 542,000
children younger than 14 years with T1D, with more than 86,000 newly Acute complications of hyperglycemia
diagnosed cases per year.9 Hyperglycemia can cause serious acute complications, presenting
as endocrine emergencies, such as diabetic ketoacidosis (DKA) and
Type 2 diabetes (T2D) is the most common form of diabetes in adults, hyperosmolar hyperglycemic state (HHS).30,31 Both these conditions
and is characterized by the presence of a state of insulin resistance are caused by relative or absolute insulin deficiency associated with
associated with a progressive loss of β-cell function.10 In recent years, excessive counter-regulatory hormones (glucagon, growth hormone,
concomitant with the growing epidemic of childhood obesity, there has cortisol, catecholamines).
also been the emergence of T2D among adolescents. Epidemiologic
data indicate that in the US T2D now accounts for 8–87% of new cases Although both DKA and HHS can present across the whole age spectrum,
of pediatric diabetes.11,12 DKA tends to be more common in young people with diabetes, whereas
HHS is more common among older patients. 30,31 For a long time it has
Additional forms of diabetes include secondary diabetes, as a consequence been assumed that only patients with T1D were at risk of developing
of prolonged use of certain drugs, such as glucocorticoids, or occurring in DKA, whereas HHS was a typical complication of patients with T2D.
the context of other diseases, such as cystic fibrosis, Cushing’s syndrome; However, it is now clear that both conditions can occur in the context
monogenic forms of diabetes, such as neonatal diabetes or the maturity of both T1D or T2D. 30,31 In addition, it is also clear that there is some
onset diabetes of the young (MODY), due to defects in genes regulating overlap between these two conditions. Some patients with HHS,
insulin secretion; and gestational diabetes.10 especially when there is severe dehydration, can present mild or
moderate acidosis that is mainly due to hypoperfusion/lactic acidosis.
Prediabetes and other earlier forms of dysglycemia On the other hand, some patients with T1D can present some features
Prediabetes is a condition characterized by abnormal glucose of HHS, such as severe hyperglycemia. 30,31
concentrations, which however, are still below the cutoff for the diagnosis
of diabetes. Prediabetes includes two main conditions: impaired fasting Diabetic ketoacidosis
glucose (IFG), characterized by fasting glucose levels between 100 and 125 DKA is an acute life-threatening complication of diabetes, characterized
mg/dl, and impaired glucose tolerance (IGT), defined by 2-hour postload by the triad of hyperglycemia (>250 mg/dl), metabolic acidosis (decreased
glucose levels between 140 and 199 mg/dl.13,14 Based on epidemiologic pH and bicarbonates), and increased total body ketone concentration. DKA
data, about 60% of adults with T2D when assessed 5 years prior to represents the initial manifestation of T1D in 13–80% of cases and it can
diagnosis present either IGT or IGF.15 also occur in up to 25% of cases of T2D at onset. In addition, DKA is a
common complication in patients with known diabetes, where it may be
During more recent years there has been a lot of interest in identifying the consequence of poor compliance with insulin treatment, acute illness,
even earlier signs of dysglycemia, predictive of future risk of diabetes. or malfunction of diabetes care equipment.30,31 Mortality associated with
Recent reports have shown that 1-hour postload glucose concentrations DKA is predominantly related to the occurrence of cerebral edema, which
≥155 mg/dl is a predictor of future risk of T2D in adults of different ethnic occurs in 0.3–1% of patients, whereas only a minority of deaths in DKA is
backgrounds, even in the presence of normal fasting or 2-hour postload due to other causes.32
glucose levels.15–19 In addition, this glucose cutoff is able to identify subjects
with an impaired cardiometabolic profile, characterized by high blood Early identification and treatment of DKA are essential to minimize the
pressure, dyslipidemia, liver steatosis, early signs of atherosclerosis, as associated morbidity and mortality. Treatment of DKA requires strict
well as an increased mortality.20–25 monitoring of the patient, correction of hyperglycemia, acidosis and ketosis,
and replacement of fluid and electrolyte losses.30,31
In children and adolescents, data on 1-hour postload glucose are not as
extensive as in adults, but some preliminary studies have confirmed that Another important action is the identification and treatment of precipitating
a cutoff of 155 mg/dl, or even of 132 mg/dl, could predict future risk of T2D events. Prevention of DKA at diagnosis is of paramount importance and
and identify young subjects with early cardiovascular abnormalities.26,27 should be based on intensive community interventions and education of

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

Hyperosmolar hyperglycemic state


HHS is the most serious acute hyperglycemic emergency in patients
with T2D. Diagnostic criteria for this condition are glucose level >600
mg/dl and increased effective plasma osmolality >320 mOsm/kg, in the Postprandial Glucose excursion Fasting
absence of ketoacidosis.30,31 The incidence of HHS is estimated to be hyperglycemia fluctuations hyperglycemia
<1% of hospital admissions of patients with diabetes and the associated
mortality is 10–20%. There are no good data from randomized studies
on the best management of HHS, which has been mainly extrapolated
from studies of patients with DKA. In HHS, the goals of initial fluid therapy Diabetic complications
are to expand the intra- and extravascular volume, restore normal renal
perfusion, and promote a gradual decline in serum sodium concentration
and osmolality.30,31 Hyperglycemia and vascular damage
Hyperglycemia contributes to the development of vascular complications
Chronic complications of diabetes—vascular through several mechanisms: activation of the polyol and hexosamine
complications pathways, diacylglycerol-protein kinase C (DAG-PKC), increased production
Hyperglycemia is a key determinant of vascular complications of diabetes, of advanced glycation end products (AGE), increased synthesis of
also known as chronic diabetes complications.33,34 There is extensive growth factors, cytokines, and oxidative stress.28,39 The polyol pathway is
evidence indicating that both acute and chronic hyperglycemia play a key implicated in the pathogenesis of vascular complications through the action
role in the pathogenesis of these complications (see Figure 1). of aldose reductase, the first and rate-limiting enzyme in this pathway.
Aldose reductase reduces the aldehyde form of glucose to sorbitol, which
Vascular complications of diabetes are divided into “microvascular” (such is then oxidized to fructose by sorbitol dehydrogenase and then again
as retinopathy, nephropathy, and neuropathy) resulting from damage of the enters into glycolysis. In the context of hyperglycemia, the production
small vessels within the microcirculation of the kidney, retina, and neurons of sorbitol overcomes the potential of its oxidation, with its consequent
and “macrovascular,” reflecting damage of large vessels and leading to accumulation within the cells and dysregulation of the cellular osmotic
cardiovascular disease.34 status, reduction of Na+/K+-ATPase activity, cytosolic increase in NADH/
NAD+, and decrease in NADPH.28
As a result of microvascular complications, diabetes is an important
determinant of blindness, end-stage renal disease, and a variety of The hexosamine pathway converts fructose-6-phosphate into N-acetyl
debilitating neuropathies. Diabetic nephropathy is a common microvascular glucosamine, which has been implicated in the activation of the
complication of diabetes, which manifests with progressive increases in transcriptional factor Sp1, leading to increased synthesis of factors, such
urinary albumin excretion, along with changes in glomerular filtration rate, as transforming growth factor beta-1 (TGF-ß1) and plasminogen activator
ultimately leading to the development of end-stage renal disease. Diabetic inhibitor-1 (PAI-1), which in turn are associated to the development of
nephropathy represents the major cause of end-stage renal disease in both vascular complications. In addition, the hexosamine pathway is also
developed and developing countries and it is an independent risk factor for associated with increased oxidative stress and the effects of the activation
cardiovascular disease.35 of this pathway can be prevented by overexpression of antioxidants,
such as superoxide dismutase. Hyperglycemia can also stimulate de
Diabetic retinopathy is one of the leading causes of blindness in people of novo synthesis of DAG, followed by the activation of PKC, which in turn
working age. This complication can be diagnosed already after five years modulates the activity of various enzymes, including phospholipase A2,
from the onset of diabetes, and almost all patients will show variable Na+/K+-ATPase, as well as the expression of genes related to components
degrees of retinopathy after 20 years of diabetes.36 of the extracellular matrix.28

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.

Conclusions Interventions able to reduce HbA1c can reduce the development or


Hyperglycemia is a well-known metabolic derangement, which can progression of vascular complications of diabetes. Further studies are
contribute to the development of serious acute (DKA, HHS) and chronic required to clarify the impact of strategies targeting more specifically
complications (micro- and macrovascular disease). Several studies have components of acute hyperglycemia, to improve outcomes in patients
clearly shown a strong association between chronic hyperglycemia and the with diabetes.

1. Shrayyef MZ, Gerich JE, Normal Glucose Homeostasis. In Poretsky 21. Bianchi C, Miccoli R, Trombetta M, et al., Elevated 1-hour postload 41. Nathan DM, McGee P, Steffes MW, Lachin JM, DCCT/EDIC
L (ed), Principles of Diabetes Mellitus, Boston, MA: Springer US, plasma glucose levels identify subjects with normal glucose Research Group, Relationship of glycated albumin to blood
2010;19–35. tolerance but impaired β-cell function, insulin resistance, and glucose and HbA1c values and to retinopathy, nephropathy, and
2. Szablewski L, Glucose Homeostasis and Insulin Resistance, Bentham worse cardiovascular risk profile: the GENFIEV study, J Clin cardiovascular outcomes in the DCCT/EDIC study, Diabetes,
Science Publishers; 2011. doi: 10.2174/97816080518921110101. Endocrinol Metab, 2013;98:2100–5. 2014;63:282–90.
3. Aronoff SL, Berkowitz K, Shreiner B, Want L, Glucose metabolism 22. Sciacqua A, Miceli S, Carullo G, et al., One-hour postload plasma 42. Group TDC and CTR, The effect of intensive treatment of
and regulation: beyond insulin and glucagon, Diabetes Spectr, glucose levels and left ventricular mass in hypertensive patients, diabetes on the development and progression of long-term
2004;17:183–90. Diabetes Care, 2011;34:1406–11. complications in insulin-dependent diabetes mellitus,
4. Rizza RA, Mandarino LJ, Gerich JE, Dose-response characteristics 23. Sesti G, Hribal ML, Fiorentino TV, et al., Elevated 1 h postload N Engl J Med, 1993;329:977–86.
for effects of insulin on production and utilization of glucose in plasma glucose levels identify adults with normal glucose 43. Kilpatrick ES, Rigby AS, Atkin SL, The diabetes control and
man, Am J Physiol, 1981;240:E630–9. tolerance but increased risk of non-alcoholic fatty liver disease, complications trial: the gift that keeps giving, Nat Rev Endocrinol,
5. Campbell JE, Drucker DJ, Islet α cells and glucagon—critical BMJ Open Diabetes Res Care, 2014;2:e000016. 2009;5:537–45.
regulators of energy homeostasis, Nat Rev Endocrinol, 24. Orencia AJ, Daviglus ML, Dyer AR, et al., One-hour postload 44. White NH, Sun W, Cleary PA, et al., Effect of prior intensive therapy
2015;11:329–38. plasma glucose and risks of fatal coronary heart disease and in type 1 diabetes on 10-year progression of retinopathy in the
6. Giugliano D, Ceriello A, Esposito K, Glucose metabolism and stroke among nondiabetic men and women: the Chicago Heart DCCT/EDIC: comparison of adults and adolescents, Diabetes,
hyperglycemia, Am J Clin Nutr, 2008;87:217S–22S. Association Detection Project in Industry (CHA) study, J Clin 2010;59:1244–53.
7. American Diabetes Association, 2. Classification and diagnosis Epidemiol, 1997;50:1369–76. 45. Pirola L, The DCCT/EDIC study: epigenetic clues after three
of diabetes, Diabetes Care, 2017;40:S11–24. 25. Bergman M, Chetrit A, Roth J, et al., One-hour post-load plasma decades, Diabetes, 2014;63:1460–2.
8. Patterson CC, Dahlquist GG, Gyürüs E, et al., Incidence trends glucose level during the OGTT predicts dysglycemia, Diabetes Res 46. Chen Z, Miao F, Paterson AD, et al., Epigenomic profiling reveals
for childhood type 1 diabetes in Europe during 1989–2003 Clin Pract, 2016;120:221–8. an association between persistence of DNA methylation and
and predicted new cases 2005–20: a multicentre prospective 26. Manco M, Miraglia Del Giudice E, Spreghini MR, et al., 1-Hour metabolic memory in the DCCT/EDIC type 1 diabetes cohort,
registration study, Lancet, 2009;373:2027–33. plasma glucose in obese youth, Acta Diabetol, 2012;49:435–43. Proc Natl Acad Sci, 2016;201603712.
9. IDF diabetes atlas - Home [Internet], 2017. Available at: 27. Tfayli H, Jung Lee S, Bacha F, Arslanian S, One-hour plasma 47. Zhong X, Liao Y, Chen L, et al., The microRNAs in the
www.diabetesatlas.org/ (accessed February 26, 2017). glucose concentration during the OGTT: what does it tell about pathogenesis of metabolic memory, Endocrinology,
10. American Diabetes Association, 2. Classification and diagnosis of β-cell function relative to insulin sensitivity in overweight/obese 2015;156:3157–68.
diabetes, Diabetes Care, 2017;40:S11–24. children?, Pediatr Diabetes, 2011;12:572–9. 48. Intensive blood-glucose control with sulphonylureas or
11. D’Adamo E, Caprio S, Type 2 diabetes in youth: epidemiology and 28. Brownlee M, The pathobiology of diabetic complications: a insulin compared with conventional treatment and risk of
pathophysiology, Diabetes Care, 2011;34:S161–5. unifying mechanism, Diabetes, 2005;54:1615–25. complications in patients with type 2 diabetes (UKPDS 33).
12. Nadeau KJ, Anderson BJ, Berg EG, et al., Youth-onset type 2 29. Orasanu G, Plutzky J, The pathologic continuum of diabetic UK Prospective Diabetes Study (UKPDS) Group, Lancet,
diabetes consensus report: current status, challenges, and vascular disease, J Am Coll Cardiol, 2009;53:S35–42. 1998;352:837–53.
priorities, Diabetes Care, 2016;39:1635–42. 30. Umpierrez G, Korytkowski M, Diabetic emergencies — ketoacidosis, 49. Nathan DM, Singer DE, Hurxthal K, Goodson JD, The clinical
13. Unwin N, Shaw J, Zimmet P, Alberti KG, Impaired glucose tolerance hyperglycaemic hyperosmolar state and hypoglycaemia, Nat Rev information value of the glycosylated hemoglobin assay,
and impaired fasting glycaemia: the current status on definition Endocrinol, 2016;12:222–32. N Engl J Med, 1984;310:341–6.
and intervention, Diabet Med, 2002;19:708–23. 31. Steenkamp DW, Alexanian SM, McDonnell ME, Adult 50. Tahara Y, Shima K, The response of GHb to stepwise plasma
14. Abdul-Ghani MA, Lyssenko V, Tuomi T, et al., The shape of plasma hyperglycemic crisis: a review and perspective, Curr Diab Rep, glucose change over time in diabetic patients, Diabetes Care,
glucose concentration curve during OGTT predicts future risk of 2013;13:130–7. 1993;16:1313–4.
type 2 diabetes, Diabetes Metab Res Rev, 2010;26:280–6. 32. Wolfsdorf JI, Allgrove J, Craig ME, et al., Diabetic ketoacidosis 51. Marcovecchio ML, Dalton RN, Chiarelli F, Dunger DB, A1C variability
15. Abdul-Ghani MA, Williams K, DeFronzo RA, Stern M, What is the best and hyperglycemic hyperosmolar state, Pediatr Diabetes, as an independent risk factor for microalbuminuria in young
predictor of future type 2 diabetes?, Diabetes Care, 2007;30:1544–8. 2014;15:154–79. people with type 1 diabetes, Diabetes Care, 2011;34:1011–3.
16. Abdul-Ghani MA, Abdul-Ghani T, Ali N, Defronzo RA, One-hour 33. Marcovecchio ML, Tossavainen PH, Dunger DB, Prevention and 52. Gorst C, Kwok CS, Aslam S, et al., Long-term glycemic variability
plasma glucose concentration and the metabolic syndrome treatment of microvascular disease in childhood type 1 diabetes, and risk of adverse outcomes: a systematic review and
identify subjects at high risk for future type 2 diabetes, Diabetes Br Med Bull, 2010;94:145–64. meta-analysis, Diabetes Care, 2015;38:2354–69.
Care, 2008;31:1650–5. 34. Orasanu G, Plutzky J, The pathologic continuum of diabetic 53. Monnier L, Lapinski H, Colette C, Contributions of fasting and
17. Abdul-Ghani MA, Lyssenko V, Tuomi T, et al., Fasting versus vascular disease, J Am Coll Cardiol, 2009;53:S35–42. postprandial plasma glucose increments to the overall diurnal
postload plasma glucose concentration and the risk for future 35. Gross JL, de Azevedo MJ, Silveiro SP, et al., Diabetic nephropathy: hyperglycemia of type 2 diabetic patients: variations with
type 2 diabetes: results from the Botnia study, Diabetes Care, diagnosis, prevention, and treatment, Diabetes Care, 2005;28:164–76. increasing levels of HbA(1c), Diabetes Care, 2003;26:881–5.
2009;32:281–6. 36. Solomon SD, Chew E, Duh EJ, et al., Diabetic retinopathy: a 54. Suh S, Kim JH, Glycemic variability: how do we measure it and
18. Alyass A, Almgren P, Akerlund M, et al., Modelling of OGTT curve position statement by the American Diabetes Association, why is it important?, Diabetes Metab J, 2015;39:273.
identifies 1 h plasma glucose level as a strong predictor of Diabetes Care, 2017;40:412–8. 55. Nalysnyk L, Hernandez-Medina M, Krishnarajah G, Glycaemic
incident type 2 diabetes: results from two prospective cohorts, 37. Pop-Busui R, Boulton AJM, Feldman EL, et al., Diabetic variability and complications in patients with diabetes mellitus:
Diabetologia, 2014;58:87–97. neuropathy: a position statement by the American Diabetes evidence from a systematic review of the literature, Diabetes
19. Jagannathan R, Sevick MA, Li H, et al., Elevated 1-hour plasma Association, Diabetes Care, 2017;40:136–54. Obes Metab, 2010;12:288–98.
glucose levels are associated with dysglycemia, impaired 38. Duca L, Sippl R, Snell-Bergeon JK, Is the risk and nature of 56. Smith-Palmer J, Brändle M, Trevisan R, et al., Assessment of the
beta-cell function, and insulin sensitivity: a pilot study from a real CVD the same in Type 1 and Type 2 diabetes?, Curr Diab Rep, association between glycemic variability and diabetes-related
world health care setting, Endocrine, 2015;52:172–5. 2013;13:350–61. complications in type 1 and type 2 diabetes, Diabetes Res Clin
20. Succurro E, Marini MA, Arturi F, et al., Elevated one-hour post-load 39. Forbes JM, Cooper ME, Mechanisms of diabetic complications, Pract, 2014;105:273–84.
plasma glucose levels identifies subjects with normal glucose Physiol Rev, 2013;93:137–88. 57. Kilpatrick ES, Rigby AS, Atkin SL, The effect of glucose variability
tolerance but early carotid atherosclerosis, Atherosclerosis, 40. Pirola L, Nathan D, Zinman B, et al., The DCCT/EDIC study: on the risk of microvascular complications in Type 1 diabetes,
2009;207:245–9. epigenetic clues after three decades, Diabetes, 2014;63:1460–2. Diabetes Care, 2006;29:1486–90.

US E NDO CRIN O L OG Y 5

You might also like