Diabetes

1. In-hospital metabolic regulation in patients with a
diabetic foot ulcer: is it worthwhile?
Aoife M Egan
Sean F Dinneen*
Galway University Hospitals and
National University of Ireland
Galway,Galway, Ireland
*Correspondence to: Sean F
Dinneen, Head of School of
Medicine, Clinical Science Institute,
Newcastle Road, Galway, Ireland.
Email: sean.dinneen@nuigalway.ie
Keywords diabetic foot; ulceration;
hospitalization; metabolic control;
glucose control
Abstract
It is well established that hyperglycaemia is associated with many negative
cardiovascular and immunological effects. Because of the high prevalence of
underlying vascular disease along with associated infection, patients with
diabetic foot ulcers are especially vulnerable to these adverse consequences.
While studies consistently demonstrate worse outcomes in the setting of
hyperglycaemia during hospitalization, multiple trials examining the effects
of intensive glycaemic control reveal mixed results. In particular, effects on
mortality are varied, and although there may be some benefit in the setting
of infection, hypoglycaemia is a concern when glucose levels are treated down
to the normoglycaemic range. Therefore, although metabolic regulation is
worthwhile theoretically, the optimal intensity of control is unclear. There is
a need for future research to clarify the benefits and risks associated with strict
metabolic control in patients with diabetic foot ulceration. In the interim rec-
ommendations from international guidelines should be followed; these advise
pre-meal glucose targets of <7.8 mmol/L and random targets of <10.0 mmol/L
in general medical and surgical settings. Copyright © 2016 John Wiley & Sons, Ltd.
Introduction
In the UK, the North-West Diabetes Foot Care Study found the average annual
incidence of diabetic foot ulceration to be 2.2%, a rate similar to other studies
including the West of Ireland Diabetes Foot Study that reported an annual
incidence of 2.6% [1–4]. Further work reveals that hospital admission for
diabetic foot disease in the UK resulted in 184.1 bed days per 1000 people with
diabetes per year [5]. A formal prospective study reported large differences in
practice and clinical outcomes between 14 specialist centres throughout
Europe for patients with diabetic foot ulceration [6,7]. Nevertheless, it is
evident that once patients are hospitalized an inpatient foot service should
be available to prevent problems, provide curative measures and optimize
the transition to outpatient care [8]. This team should be expert on clinical
pathways and therapeutic goals including in-hospital metabolic regulation. In
this article we will review the rationale and available evidence surrounding
in-hospital metabolic regulation with a focus on glycaemic control.
Foot ulceration and glycaemic control
In the West of Ireland Diabetes Foot Study, 23–25% of participants had sensory
dysfunction, and 18–39% had evidence of vascular impairment [4]. These
SUPPLEMENT ARTICLE
Copyright © 2016 John Wiley & Sons, Ltd.
DIABETES/METABOLISM RESEARCH AND REVIEWS
Diabetes Metab Res Rev 2016; 32(Suppl. 1): 297–302.
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2741

2. findings are similar to Scottish and English data reporting
abnormal pedal pulse palpation in 17–21% and impaired
cutaneous pressure perception in 21–23% of patients
[1,9]. These complications are precursors to foot ulcera-
tion and are strongly associated with poor glycaemic
control and other adverse arterial risk factors including
smoking and dyslipidaemia [10]. However, once ulcera-
tion becomes established the role of glycaemic control in
predicting outcome is ambiguous, and studies differ in
terms of their results. Apelqvist et al. prospectively exam-
ined 314 patients with diabetic foot ulceration and found
no difference in glycosylated haemoglobin (HbA1c) levels
between those who healed primarily and those who
healed after amputation [11]. Subsequently Marston
et al. examined 245 patients with diabetic foot ulcer and
noted improved healing among those who had a stable
or reduction in HbA1c for the duration of the study com-
pared with those whose HbA1c increased [12]. More re-
cently Tabur et al. reported that there was no association
between duration of diabetes or glucose control and
amputation and length of hospital stay in diabetic patients
with acute foot ulceration [13]. In general it would ap-
pear that alternative risk factors such as older age, male
gender, ulcer size and inflammatory markers are more
predictive of outcome for diabetic foot ulceration than
glycaemic control as measured by HbA1c [7,13]. Neverthe-
less, it is necessary to further explore the issue of acute
hyperglycaemia and its impact on outcome. This is partic-
ularly important among those requiring hospitalization,
as this cohort will have regular glucose monitoring and
the opportunity to have frequent modifications to their
treatment regimens.
Acute hyperglycaemia and poor
outcomes: mechanisms of harm
Patients with diabetes are more likely to be hospitalized
and experience a longer duration of hospital stay than
those without [14]. While this information refers to the pop-
ulation with diabetes as a whole, it encompasses those with
diabetic foot ulceration. The presence of hyperglycaemia dur-
ing a hospital stay is noted to be an independent marker of
poor outcome [15–17]. Umpierrez et al. demonstrated that
in-hospital hyperglycaemia is present in 38% patients admit-
ted to hospital of whom 26% had a known history of diabetes
[15]. The remaining patients fall into the category of stress
hyperglycaemia, defined as a transient increase in blood glu-
cose concentration during acute physiological illness [15].
Stress-induced hyperglycaemia is associated with increased
counter-regulatory hormones, lactate and insulin resistance,
and while it possibly also occurs in patients with pre-existing
diabetes, it is difficult to define in that setting as the
unstressed baseline concentration of glucose is unknown
[15,18]. Patients with newly diagnosed hyperglycaemia
may have a higher mortality rate than those with a known
history of diabetes or normoglycaemia, and this may be
because of the fact that new hyperglycaemia represents a
marker of more severe illness [15,18]. The mechanism of
hyperglycaemia-induced harm has been extensively studied
and is related to the effects of elevated glucose on the
immune and vascular systems [19].
There is a key relationship between hyperglycaemia
and infection with studies consistently demonstrating that
hyperglycaemia causes immunosuppression primarily be-
cause of neutrophil and monocyte dysfunction [20–22].
One study demonstrated defective neutrophil phagocytic
function in the setting of hyperglycaemia and further
work revealed improvements in leukocyte dysfunction
with treatment of hyperglycaemia [23,24]. This informa-
tion is particularly pertinent to foot ulcers where infection
plays a large role in the associated morbidity. Indeed, at
the time of presentation more than half of diabetic foot
ulcers are clinically infected [25–27].
Acute hyperglycaemia has multiple effects on the car-
diovascular system [19]. Marfella and colleagues demon-
strated the broad clinical effects of acute hyperglycaemia
in patients with diabetes including elevations in systolic
and diastolic blood pressure, heart rate and plasma
catecholamines [28]. This connection between acute
hyperglycaemia and vascular disruption likely involves
inflammatory changes [19]. Glucose-induced elevations
in interleukin-6, interleukin-18 and tumour necrosis
factor-alpha are well-recognized, and these factors are
associated with negative cardiovascular effects including
destabilization of atherosclerotic plaque [29,30]. Finally,
hyperglycaemia also has a negative effect on ischemic
brain tissue and enhanced acidosis exaggerating ischemic
neuronal injury is a possible mechanism of injury [31]. In
the setting of diabetic foot ulceration, one would be
particularly concerned regarding these cardiovascular
effects given the presence of peripheral vascular disease
and often underlying cardiac disease in this population.
Bearing this information in mind, stringent glycaemic
control to avoid the harmful effects of hyperglycaemia
seems like a reasonable approach to care for the hospital-
ized patient with diabetic foot ulceration. Unfortunately,
clinical studies reveal mixed results as described below.
Does treatment of hyperglycaemia
improve clinical outcomes?
(i) Patients with acute ischaemic events
While hyperglycaemia is clearly detrimental, there is a
dispute regarding the impact and optimal intensity of
in-hospital glucose control. A paucity of literature exists
298 A. M. Egan and S. F. Dinneen
Copyright © 2016 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2016; 32(Suppl. 1): 297–302.
DOI: 10.1002/dmrr

3. in patients with a diabetic foot ulcer specifically; however,
we may draw from the evidence involving more general
groups of inpatients with and without diabetes: those
with cardiovascular/cerebrovascular disease and those
with general medical/surgical admissions.
The Diabetes Mellitus, Insulin Glucose Infusion in
Acute Myocardial Infarction study randomly allocated
620 patients with diabetes mellitus and acute myocardial
infarction to either standard treatment plus insulin–
glucose infusion for at least 24 h followed by multi-dose
insulin treatment for at least 3 months or standard treat-
ment with insulin therapy only if indicated. The target blood
glucose level for the infusion group was 7.0–10.9 mmol/L.
The investigators demonstrated that insulin–glucose
infusion followed by intensive subcutaneous insulin im-
proved long-term survival and the effects seen at one year
continued for at least 3.5 years with an absolute reduction
in mortality of 11% [32]. Although it was not entirely clear
if the benefit was because of the acute control or the follow
on therapy, the Diabetes Mellitus, Insulin Glucose Infusion
in Acute Myocardial Infarction trial was followed by a
change in clinical practice by many clinicians – until the
publication of the Diabetes Mellitus, Insulin Glucose
Infusion in Acute Myocardial Infarction 2 trial in 2005. In
this study, three treatment strategies were compared and
included: (1) acute insulin–glucose infusion followed
by insulin-based long-term glucose control; (2) insulin–
glucose infusion followed by standard glucose control
and (3) routine metabolic management according to local
practice. This study was stopped prematurely because of a
failure to recruit adequate participants and a resultant
reduction in the overall power of the study. However,
glycaemic control was similar in all three groups, and mor-
tality and morbidity did not differ significantly between
groups [33].
The Hyperglycaemia: Intensive Insulin Infusion In
Infarction (HI-5) study aimed to clarify this conflicting
evidence. In this trial, 240 subjects presenting with acute
myocardial infarction and blood glucose level greater
than or equal to 7.8 mmol/L were randomized to receive
insulin–dextrose infusion therapy for at least 24 h to
maintain a blood glucose levels of less than 10 mmol/L
or conventional therapy. After this time, the patients were
managed by standard care at the discretion of the treating
physician. The investigators found that insulin–dextrose
infusion did not reduce mortality at the inpatient stage
or at three and six months. However, they did note that
there was a lower incidence of cardiac failure (12.7 versus
22.8%) and re-infarction within three months (2.4 versus
6.1%) in the group receiving the infusion. Additionally,
mortality was lower among subjects with a mean blood
glucose over the first 24 h of ≤8 mmol/L compared
to those with a mean blood glucose level of >8 mmol/L
(2 versus 11%) [34].
These cardiovascular studies reflect again the negative
effects of hyperglycaemia during hospitalization but high-
light difficulties in yielding a positive effect from interven-
tions aimed at achieving intensive glycaemic control or
modulation of the glucose/insulin/potassium milieu.
Hyperglycaemia is common after acute ischemic stroke,
and the majority of clinical trials have concluded that it in-
dependently predicts increased stroke mortality [35–38].
With many prior studies in this area, a 2013 Cochrane
review aimed to amalgamate this evidence to determine
whether treating hyperglycaemia following stroke
reduces mortality and improves functional outcomes.
The authors included 11 randomized, controlled trials
involving 1583 participants and found that there was no
difference between treatment and control groups in the
outcomes of death or dependency or final neurological
deficit. The rate of symptomatic hypoglycaemia was
higher in the intervention group. The findings did not
change in the subgroup analysis of those with and with-
out diabetes mellitus [31].
(ii) Intensive care unit studies
There are several randomized controlled trials looking
at the effects of treating hyperglycaemia in patients with
and without diabetes in medical and surgical intensive
care units. Van den Berghe and colleagues completed a
prospective, randomized controlled study involving 1548
adults admitted to a surgical intensive care unit who were
receiving mechanical ventilation. Patients were randomly
assigned to receive intensive insulin therapy (target glu-
cose 4.4–6.1 mmol/L) or conventional treatment (insulin
infusion only if the blood glucose level exceeded
12.0 mmol/L and maintenance of glucose at 10.0–
11.1 mmol/L). Intensive insulin therapy reduced mortal-
ity during intensive care from 8% with conventional
treatment to 4.6% (p < 0.04). The greatest reduction in
mortality involved deaths because of multiple-organ
failure with a proven septic focus [16]. In this study, a
history of diabetes or hyperglycaemia at the time of
admission did not affect measures of morbidity.
When the same investigators completed a similar trial
involving 1200 patients in the medical intensive care unit,
they noted that while intensive insulin therapy signifi-
cantly reduced morbidity, it did not have a positive effect
on mortality [39]. This latter group of patients had more
frequent episodes of biochemical hypoglycaemia and
logistic regression analysis identified hypoglycaemia as
an independent risk factor for death.
Brunkhorst et al. evaluated the role of intensive versus
conventional insulin therapy and pentastarch versus mod-
ified Ringer’s lactate for resuscitation in severe sepsis
using a two-by-two factorial trial design. While this trial
was stopped early for safety reasons, 537 patients
Diabetic Foot: In-Hospital Control 299
Copyright © 2016 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2016; 32(Suppl. 1): 297–302.
DOI: 10.1002/dmrr

4. completed the study protocol. They found no benefit of in-
tensive insulin therapy in terms of mortality and the rate
of severe hypoglycaemia (2.2 mmol/L) was significantly
higher in the intensive therapy group (17.0 versus 4.1%,
p < 0,01) as was the rate of serious adverse events (10.9
versus 5.2%, p = 0.01). In total, 30.4% participants had a
pre-existing diagnosis of diabetes mellitus, and 11.4%
were hospitalized for a bone or soft tissue infection [40].
More recently in 2008, De La Rosa and colleagues ran-
domly assigned 504 patients to either intensive insulin
therapy (glucose target 4.4–6.1 mmol/L) or standard
insulin therapy (10.0–11.1 mmol/L). These patients were
admitted to a medical–surgical intensive care unit, and
approximately 12% had a pre-existing diagnosis of diabe-
tes mellitus. Established infection was a common reason
for admission (33%). There was no difference in morbidity
and mortality between the groups but there was an increase
in rates of hypoglycaemia (<40 mg/dL) in the intensive
insulin group (relative risk 5.04, 95% CI 1.20–21.12). The
intervention did not significantly decrease the rate of inten-
sive care unit-acquired infections [41]. The Normoglycaemia
in Intensive Care Evaluation-Survival Using Glucose Algo-
rithm Regulation (NICE-SUGAR) study investigators evalu-
ated over 6000 patients randomizing to either intensive
glucose control (target 4.5–6.0 mmol/L) or conventional
glucose control (<10.0 mmol/L). Intensive glucose control
increased mortality (odds ratio 1.14, 95% CI 1.02–1.28,
p=0.02), and the treatment effect did not differ
significantly between surgical and medical patients and
those with and without diabetes. Severe hypoglycaemia
was significantly more common in the intensive-control
group (6.8 versus 0.5%, p< 0.001) [42].
A 2008 meta-analysis concluded that tight glucose
control in critically ill adult patients is not associated with
significantly reduced hospital mortality but is associated
with an increased risk of hypoglycaemia [43]. A subse-
quent meta-analysis including the NICE-SUGAR study
data again concluded that intensive insulin therapy signif-
icantly increased the risk of hypoglycaemia and conferred
no overall mortality benefit among critically ill patients.
The authors did note that this therapy may be beneficial
to those admitted to a surgical intensive care unit [44].
(iii) General hospital ward studies
Several studies have examined the effects of intensive
glycaemic control on outcomes of patients hospitalized
on general wards, and in 2011, an Endocrine Society task
force conducted a systematic review and meta-analysis
to summarize available evidence. They included nine
randomized and ten observational studies and found that
intensive glycaemic control was not associated with a sig-
nificant effect on the risk of death, myocardial infarction
or stroke. They did note a trend for increased risk of
hypoglycaemia (relative risk 1.58; 95% CI 0.97–2.57)
but also reported an associated decreased risk of infection
(relative risk 0.41; 95% CI 0.21–0.77) with intensive
glycaemic control. However, the latter findings were
mainly driven by studies in surgical settings [45].
To summarize the evidence, although there is a strong
association between hyperglycaemia in hospital and ad-
verse outcomes, the optimal intensity of inpatient glucose
control is unclear. There is concern that regimens leading
to intensive control are associated with increased risk of
severe hypoglycaemia. On the other hand, there is a sug-
gestion that more intensive glycaemic control is associ-
ated with reduced infection risk, which is particularly
important in the case of diabetic foot ulceration. The
reasons underlying the stark contrasts between many of
these study outcomes are unclear but likely lie in the
heterogeneity of study design. For example, parenteral
hyperalimentation was the rule in the single-centre Van
den Berghe trial, and enteral nutrition was the norm in
the multicentre NICE-SUGAR study [46]. Furthermore,
the glycaemic targets differ in many of the studies, and
therefore the risk of hypoglycaemia is not uniform. In
light of these conflicting data, we believe that the consen-
sus opinion of the American Association of Clinical
Endocrinologists/American Diabetes Association and the
Endocrine Society Practice Guideline on in-patient
glycaemic control provide reasonable targets applicable
to patients with active foot ulceration. Both guidelines
set pre-meal targets at <7.8 mmol/L and random blood
glucose of <10.0 mmol/L. The American Association of
Clinical Endocrinologists/American Diabetes Association
guideline recommends that in critically ill patients, insulin
infusion should commence when glucose levels rise above
10.0 mmol/L with a treatment target of 7.8–10.0 mmol/L
[14,47]. These targets should reduce side effects of
hyperglycaemia and facilitate wound healing while mini-
mizing the risk of hypoglycaemia in these patients. The
importance of frequent blood glucose monitoring during
insulin treatment must be emphasized, especially in frail
and elderly patients who are particularly vulnerable to
side effects of hypoglycaemia.
Role of other metabolic factors
Diabetic foot ulcer patients typically have multiple co-
morbidities, and the hospital admission should be taken
as an opportunity to address these issues. In a 2012
meta-analysis, Brownrigg and colleagues noted that dia-
betic foot ulceration was associated with an increased risk
of all cause mortality (RR 1.89, 95% CI 1.60–2.23), fatal
myocardial infarction (2.22, 95% CI 1.09–4.53) and fatal
stroke (1.41, 95% CI 0.61–3.24) [48]. Another study
noted that 84% of subjects with diabetic foot ulceration
reported having at least one complication of diabetes,
300 A. M. Egan and S. F. Dinneen
Copyright © 2016 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2016; 32(Suppl. 1): 297–302.
DOI: 10.1002/dmrr

5. e.g. cardiovascular disease, nephropathy or retinopathy
[49]. It is important that appropriate consultative services
such as cardiology, nephrology and infectious diseases are
available to assist in the multidisciplinary management
and facilitate aggressive risk factor modification where
possible [8].
A role for future research?
Is metabolic control worthwhile in hospitalized patients
with a diabetic foot ulcer? In order to answer this ques-
tion, we believe that further, condition-specific research
is necessary. A randomized, controlled trial of tight versus
less tight glycaemic control involving patients hospitalized
for management of diabetic foot ulceration would be
ideal. This study should be multicentre and involve pa-
tients of varied age, gender and ethnicity. Use of the pop-
ulation; intervention; comparison; outcome; time formula
facilitates development of the research question(s) [50].
Standard care should be compared to intensive glycaemic
control with insulin therapy. Wound healing at 24 weeks
would be a suitable primary outcome, and secondary out-
comes could include incidence of hypoglycaemia, duration
of hospital stay and antibiotic therapy, cardiovascular events
and cause-specific death. Results obtained from this trial
would provide information specific to the population of
interest and reduce the need to draw inferences from more
generalized patient groups.
Conclusions
Patients requiring hospitalization for diabetic foot ulcera-
tion are a vulnerable group and typically have multiple
co-morbidities. Pre-existing vascular disease and associ-
ated infection place them at particular risk of
hyperglycaemia-related side effects. Although evidence
supporting intensive, in-hospital metabolic control is
limited, the available evidence suggests that pre-meal
glucose targets of <7.8 mmol/L and random targets of
<10.0 mmol/L are reasonable for general medical and
surgical settings. These goals will avoid significant
hyperglycaemia while minimizing the risk of
hypoglycaemia and are practically achievable. It is hoped
that future research in the area of glucose control in the
hospital setting will involve patients with diabetic foot
ulceration specifically to further clarify this complex issue.
Conflict of interest
The authors declare no conflict of interest in relation to
this manuscript.
References:
1. Abbott CA, Carrington AL, Ashe H, et al.
The North-West Diabetes Foot Care
Study: incidence of, and risk factors for,
new diabetic foot ulceration in a com-
munity-based patient cohort. Diabet
Med 2002; 19(5): 377–384.
2. Moss SE, Klein R, Klein BE. The preva-
lence and incidence of lower extremity
amputation in a diabetic population.
Arch Intern Med 1992; 152(3): 610–616.
3. Ramsey SD, Newton K, Blough D, et al.
Incidence, outcomes, and cost of foot
ulcers in patients with diabetes. Diabetes
Care 1999; 22(3): 382–387.
4. Hurley L, Kelly L, Garrow AP, et al. A
prospective study of risk factors for foot
ulceration: the West of Ireland Diabe-
tes Foot Study. QJM 2013; 106(12):
1103–1110.
5. Follett P, Young B, Holman N. Hospital
admissions for diabetic foot disease.
Diabet Med 2012 suppl; 29(1): 14.
6. Holman N, Young B, Stephens H,
Jeffcoate W. Members of the National
Foot Care Audit Steering Group. Pilot
study to assess measures to be used in
the prospective audit of the manage-
ment of foot ulcers in people with diabe-
tes. Diabet Med 2015; 32(1): 78–84.
7. Prompers L, Schaper N, Apelqvist J, et al.
Prediction of outcome in individuals
with diabetic foot ulcers: focus on the
differences between individuals with
and without peripheral arterial disease.
EURODIALE Stud Diabetologia 2008;
51(5): 747–755.
8. Wukich DK, Armstrong DG, Attinger CE,
et al. Inpatient management of diabetic
foot disorders: a clinical guide. Diabetes
Care 2013; 36(9): 2862–2871.
9. Leese GP, Reid F, Green V, et al. Stratifi-
cation of foot ulcer risk in patients with
diabetes: a population-based study. Int
J Clin Pract 2006; 60(5): 541–545.
10. National Institute for Health and Care
Excellence (NICE). Type 2 diabetes foot
problems. Prevention and management
of foot problems. NICE clinical guideline
10. 2004 (modified December 2014).
http://www.nice.org.uk/guidance/cg10
(accessed 22/02/2015).
11. Apelqvist J, Agardh CD. The association
between clinical risk factors and out-
come of diabetic foot ulcers. Diabetes
Res Clin Pract 1992; 18(1): 43–53.
12. Marston WA, Group DDFUS. Risk fac-
tors associated with healing chronic
diabetic foot ulcers: the importance of
hyperglycemia. Ostomy Wound Manage
2006; 52(3): 26–39.
13. Tabur S, Eren MA, Celik Y, et al. The ma-
jor predictors of amputation and length
of stay in diabetic patients with acute
foot ulceration. Wien Klin Wochenschr
2015; 127(1–2): 45–50.
14. Moghissi ES, Korytkowski MT, DiNardo
M, et al. American Association of Clinical
Endocrinologists and American Diabetes
Association consensus statement on in-
patient glycemic control. Diabetes Care
2009; 32(6): 1119–113.
15. Umpierrez GE, Isaacs SD, Bazargan N,
You X, Thaler LM, Kitabchi AE. Hyper-
glycemia: an independent marker of
in-hospital mortality in patients with
undiagnosed diabetes. J Clin Endocrinol
Metab 2002; 87(3): 978–982.
16. van den Berghe G, Wouters P, Weekers
F, et al. Intensive insulin therapy in criti-
cally ill patients. N Engl J Med 2001;
345(19): 1359–1367.
17. O’Sullivan EP, Duignan J, O’Shea P,
Griffin D, Dinneen SF. Evaluating
hyperglycaemia in the hospitalised pa-
tient: towards an improved system for
classification and treatment. Ir J Med
Sci 2014; 183(1): 65–69.
Diabetic Foot: In-Hospital Control 301
Copyright © 2016 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2016; 32(Suppl. 1): 297–302.
DOI: 10.1002/dmrr

6. 18. Capes SE, Hunt D, Malmberg K, Gerstein
HC. Stress hyperglycaemia and in-
creased risk of death after myocardial
infarction in patients with and without
diabetes: a systematic overview. Lancet
2000; 355(9206): 773–778.
19. Clement S, Braithwaite SS, Magee MF,
et al. Management of diabetes and hy-
perglycemia in hospitals. Diabetes Care
2004; 27(2): 553–591.
20. Joshi N, Caputo GM, Weitekamp MR,
Karchmer AW. Infections in patients
with diabetes mellitus. N Engl J Med
1999; 341(25): 1906–1912.
21. van Oss CJ, Border JR. Influence of inter-
mittent hyperglycemic glucose levels on
the phagocytosis of microorganisms by
human granulocytes in vitro. Immunol
Commun 1978; 7(6): 669–676.
22. McManus LM, Bloodworth RC, Prihoda
TJ, Blodgett JL, Pinckard RN. Agonist-
dependent failure of neutrophil function
in diabetes correlates with extent of hy-
perglycemia. J Leukoc Biol 2001; 70(3):
395–404.
23. Davidson NJ, Sowden JM, Fletcher J.
Defective phagocytosis in insulin con-
trolled diabetics: evidence for a reaction
between glucose and opsonising proteins.
J Clin Pathol 1984; 37(7): 783–786.
24. Rassias AJ, Marrin CA, Arruda J,
Whalen PK, Beach M, Yeager MP. Insulin
infusion improves neutrophil function in
diabetic cardiac surgery patients. Anesth
Analg 1999; 88(5): 1011–1016.
25. Frykberg RG. An evidence-based ap-
proach to diabetic foot infections. Am J
Surg 2003; 186(5A): 44S–54S discus-
sion 61S–64S.
26. Lavery LA, Armstrong DG, Wunderlich
RP, Mohler MJ, Wendel CS, Lipsky BA.
Risk factors for foot infections in individ-
uals with diabetes. Diabetes Care 2006;
29(6): 1288–1293.
27. Prompers L, Huijberts M, Apelqvist J,
et al. High prevalence of ischaemia, infec-
tion and serious comorbidity in patients
with diabetic foot disease in Europe.
Baseline results from the Eurodiale
study. Diabetologia 2007; 50(1): 18–25.
28. Marfella R, Nappo F, De Angelis L,
Paolisso G, Tagliamonte MR, Giugliano
D. Hemodynamic effects of acute hyper-
glycemia in type 2 diabetic patients.
Diabetes Care 2000; 23(5): 658–663.
29. Esposito K, Nappo F, Marfella R, et al.
Inflammatory cytokine concentrations
are acutely increased by hyperglycemia
in humans: role of oxidative stress.
Circulation 2002; 106(16): 2067–2072.
30. Mallat Z, Corbaz A, Scoazec A, et al.
Expression of interleukin-18 in human
atherosclerotic plaques and relation to
plaque instability. Circulation 2001;
104(14): 1598–1603.
31. Bellolio MF, Gilmore RM, Ganti L. Insu-
lin for glycaemic control in acute ischae-
mic stroke. Cochrane Database Syst Rev
2014; 1: CD005346.
32. Malmberg K, Rydén L, Efendic S, et al.
Randomized trial of insulin–glucose in-
fusion followed by subcutaneous insulin
treatment in diabetic patients with acute
myocardial infarction (DIGAMI study):
effects on mortality at 1 year. J Am Coll
Cardiol 1995; 26(1): 57–65.
33. Malmberg K, Rydén L, Wedel H, et al.
Intense metabolic control by means of
insulin in patients with diabetes mellitus
and acute myocardial infarction (DIGAMI
2): effects on mortality and morbidity.
Eur Heart J 2005; 26(7): 650–661.
34. Cheung NW, Wong VW, McLean M. The
Hyperglycemia: Intensive Insulin Infusion
in Infarction (HI-5) study: a randomized
controlled trial of insulin infusion therapy
for myocardial infarction. Diabetes Care
2006; 29(4): 765–770.
35. Capes SE, Hunt D, Malmberg K, Pathak
P, Gerstein HC. Stress hyperglycemia
and prognosis of stroke in nondiabetic
and diabetic patients: a systematic over-
view. Stroke 2001; 32(10): 2426–2432.
36. Gray CS, Taylor R, French JM, et al. The
prognostic value of stress hyperglycaemia
and previously unrecognized diabetes in
acute stroke. Diabet Med 1987; 4(3):
237–240.
37. Melamed E. Reactive hyperglycaemia in
patients with acute stroke. J Neurol Sci
1976; 29(2–4): 267–275.
38. Weir CJ, Murray GD, Dyker AG, Lees KR.
Is hyperglycaemia an independent pre-
dictor of poor outcome after acute stroke?
Results of a long-term follow up study.
BMJ 1997; 314(7090): 1303–1306.
39. Van den Berghe G, Wilmer A, Hermans
G, et al. Intensive insulin therapy in the
medical ICU. N Engl J Med 2006;
354(5): 449–461.
40. Brunkhorst FM, Engel C, Bloos F, et al.
Intensive insulin therapy and pentastarch
resuscitation in severe sepsis. N Engl J
Med 2008; 358(2): 125–139.
41. De La Rosa GC, Donado JH, Restrepo
AH, et al. Strict glycaemic control in
patients hospitalised in a mixed medical
and surgical intensive care unit: a
randomised clinical trial. Crit Care 2008;
12(5): R120.
42. Finfer S, Chittock DR, Su SY, et al. Inten-
sive versus conventional glucose control
in critically ill patients. N Engl J Med
2009; 360(13): 1283–1297.
43. Wiener RS, Wiener DC, Larson RJ. Ben-
efits and risks of tight glucose control
in critically ill adults: a meta-analysis.
JAMA 2008; 300(8): 933–944.
44. Griesdale DE, de Souza RJ, van Dam RM,
et al. Intensive insulin therapy and
mortality among critically ill patients: a
meta-analysis including NICE-SUGAR
study data. CMAJ 2009; 180(8): 821–827.
45. Murad MH, Coburn JA, Coto-Yglesias F,
et al. Glycemic control in non-critically
ill hospitalized patients: a systematic
review and meta-analysis. J Clin
Endocrinol Metab 2012; 97(1): 49–58.
46. Inzucchi SE, Siegel MD. Glucose control
in the ICU—how tight is too tight? N
Engl J Med 2009; 360(13): 1346–1349.
47. Umpierrez GE, Hellman R, Korytkowski
MT, et al. Management of hyperglycemia
in hospitalized patients in non-critical
care setting: an endocrine society clinical
practice guideline. J Clin Endocrinol
Metab 2012; 97(1): 16–38.
48. Brownrigg JR, Davey J, Holt PJ, et al.
The association of ulceration of the foot
with cardiovascular and all-cause mor-
tality in patients with diabetes: a meta-
analysis. Diabetologia 2012; 55(11):
2906–2912.
49. Yekta Z, Pourali R, Ghasemi-Rad M.
Comparison of demographic and clinical
characteristics influencing health-
related quality of life in patients with
diabetic foot ulcers and those without
foot ulcers. Diabet Metab Syndr Obes
2011; 4: 393–399.
50. Haynes R. Forming Research Questions.
Clinical Epidemiology: How to do
Clinical Practice Research. Lippincott
Williams & Wilkins: Philadelphia, PA,
2006; 3–14.
302 A. M. Egan and S. F. Dinneen
Copyright © 2016 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2016; 32(Suppl. 1): 297–302.
DOI: 10.1002/dmrr