metabolic control and prevalence of microvascular complications in young danish patients with type 1...

Metabolic control and prevalence of microvascularcomplications in young Danish patients with Type 1diabetes mellitus

B. S. Olsen*, J. Johannesen², A. K. Sjùlie³, K. Borch-Johnsen², P. Hougaard§, B.Thorsteinsson¶, S. Pramming§, K. Marinelli*, H. B. Mortensen* and the Danish StudyGroup of Diabetes in Childhood**

Abstract

Aims After Danish nationwide investigations (1987, 1989) demonstrated

unacceptable blood glucose control in unselected young diabetic patients, we set

out to estimate the present glycaemic control and the prevalence of microvascular

complications in a cohort of children and adolescents participating in the two

previous studies.

Methods This follow-up represents 339 patients (47% of the inception cohort),

median age 21.1 years (range 12.0±26.9), median diabetes duration 13.2 years

(range 8.9±24.5). A standardized questionnaire, fundus photographs (with central

reading) and a physical examination were performed. HbA1c and overnight

albumin excretion rate (AER) were analysed centrally.

Results Although 88% (n = 309) of the young persons were treated with three or

more daily insulin injections, HbA1c (nondiabetic range 4.3±5.8, mean 5.3%) was

9.7 6 1.7% (mean 6 SD). Males had higher HbA1c values than females (P < 0.015).

Mean daily insulin dose was 0.92 6 0.25 IU.kg±1.24 h±1. Microalbuminuria

(AER > 20±150 mg/min) and macroalbuminuria (AER > 150 mg/min) were found in

9.0% and 3.7% of the patients, respectively, and was associated with increased

diastolic blood pressure (P < 0.01) and presence of retinopathy (P < 0.01).

Retinopathy was present in » 60% of the patients and was associated with age,

diabetes duration, HbA1c, diastolic blood pressure and AER (all P < 0.01).

Subclinical neuropathy (vibration perception threshold by biothesiometry > 6.5 V)

was found in 62% and showed a signi®cant association with age, linear height,

diastolic blood pressure (all P < 0.01) and diabetic retinopathy (P = 0.01).

Conclusions In spite of the majority of the patients being on multiple insulin

injections, only 11% had HbA1c values below 8% and the prevalence of diabetic

microvascular complications in kidneys, eyes and nerves was unacceptable high.

Diabet. Med. 16, 79±85 (1999)

Keywords adolescence, blood glucose control, microvascular complications, Type

1 diabetes mellitus

Abbreviations AER, albumin excretion rate; ACE angiotensin converting enzyme;

BMI, body mass index; CV, coef®cient of variation; DCCT, diabetes control and

complication study; DM, diabetes mellitus; SD, standard deviation; SE, standard

error; VPT, vibration perception threshold; U, units.

R

*Department of Paediatrics, Glostrup University

Hospital, ²Steno Diabetes Center, Gentofte,

Denmark

³Department of Ophthalmology, Odense

University Hospital, Odense, Denmark

§Novo Research Institute, Bagsvaerd, Denmark

¶Department of Internal Medicine F, Hillerùd

Hospital, Hillerùd, Denmark

**Members of the Danish Study Group of

Diabetes in Childhood:

Participating departments: O. Andersen (Hillerùd),

N. Birkebñk (AÊ rhus), J. Haar (Viborg), L.P. Hansen

(Sùnderborg), K. Henriksen (Nykùbing Falster),

B. Brock Jacobsen (Odense), T. Klinge (Holbñk),

S. Krabbe (Nñstved), J. Kreutzfeldt (Kolding),

H.T. Lund (Randers), J. Lùchte (Bornholm),

B. Marner (Sundby), H.B. Mortensen (Glostrup),

M. Muff (Hjùrring), I. Leer Pedersen (Herning), Jùrn

Nerup (Steno Diabetes Center), I.M. Nielsen

(Hvidovre), C. Pedersen (Esbjerg), M. Rix (AÊ lborg),

H. Sardemann (Roskilde).

Received 6 March 1998; revised 3 September

1998; accepted 7 September 1998

Correspondence to: Dr Birthe Susanne Olsen, Department of Paediatrics,

Glostrup University Hospital, DK-2600 Glostrup, Denmark.

ã 1999 British Diabetic Association. Diabetic Medicine, 16, 79±85 79

Introduction

The Diabetes Control and Complications Trial (DCCT)

demonstrated that hyperglycaemia plays a prominent role in

the development of diabetic microvascular complications in

adolescents [1] and adults [2] with Type 1 diabetes mellitus

(DM). It was further shown that intensive diabetes manage-

ment improved glycaemic control and postponed the devel-

opment and progression of diabetic complications. However,

results from the adolescent cohort in the DCCT showed a

threefold increase in the risk of severe hypoglycaemic events.

Weight gain was another undesirable side-effect which may

in¯uence young patients adherence with the therapeutical

regimen [1,2].

Nationwide investigations in Denmark (1987, 1989) have

previously demonstrated unacceptable metabolic control in

unselected young diabetic patients [3±5], even though a large

proportion was on multiple insulin injection schedules. The

aim of the this 8 years follow-up study was to evaluate the

present metabolic control and the prevalence of microvascular

complications in a cohort of young Danish Type 1 diabetic

patients.

Patients and methods

The present nationwide multicentre cross-sectional study

involved 19 paediatric departments and ®ve departments

of internal medicine. All 720 children and adolescents

participating in the two previous nationwide studies in

1987 [4] and 1989 [5] were identi®ed and eligible for the

present study. Three-hundred and thirty-nine patients

(47.0%) accepted to participate and completed the study,

thus comprising the study population. Among the

remaining 381 patients, 106 patients initially agreed to

participate but failed to attend, while 275 patients did

not participate for various reasons (Fig. 1). Data collected

in 1987 and 1989 (age, sex, duration of diabetes, insulin

dose, HbA1c, body mass index (BMI), blood pressure and

albumin excretion rate (AER)) from the participating

patients were compared with the data of the nonpartici-

pating patients to determine whether any selection bias

existed.

Information on sex, age, diabetes duration, insulin dose,

height and body weight was recorded in all 339 patients.

There were 159 females and 180 males with a median

age of 21.1 years (range 12.0±26.9) and a median diabetes

duration of 13.2 years (range 8.9±24.5). At home the

patients collected blood samples for HbA1c determination

by a capillary blood collection system [6] and two

consecutive overnight timed urine samples for determina-

tion of AER. The blood and urine samples were collected

within 2 days and mailed together with information on

clinical data to the laboratory at the paediatric depart-

ment of Glostrup University Hospital. HbA1c was

determined by an automatic high pressure liquid chroma-

tography (Hi-AUTO A1c, mean 5.3%, normal range 4.3±

5.8). Albumin concentration was analysed by an immu-

noturbidimetric method with an interassay CV of 7% and

a detection limit of 1 mg/l [4]. Microalbuminuria was

de®ned as an overnight AER of 20±150 mg/min, and

macroalbuminuria as AER > 150 mg/min. If AER

was > 20 mg/min in one of the two samples, a third

sample was collected to determine if the patient had

microalbuminuria. The mean of the two consistent AER

values was used in the statistical analysis.

Colour retinal photographs were performed after

dilation of the pupils, by trained operators in 12

ophthalmologic departments across the country. The

photography was performed by a 40±60° retinal camera,

as described by Aldington et al. [7]. Brie¯y, the photo-

graphs included two ®elds of each eye, macular-temporal

®eld and disc/nasal ®eld, recording a retinal view of app.

80° horizontally by 45° vertically. Compared to the `gold

standard' photographic grading system of 7-®eld 30°, our

method shows a 100% agreement on detecting diabetic

retinopathy and minor disagreement in discriminating

between preproliferative and proliferative retinopathy.

All photographers received written instructions covering

all aspects of the procedure and were asked to submit test

photographs to demonstrate acceptable quality and ®eld

de®nition of photographs. Assessment of diabetic retino-

pathy was carried out centrally by a trained reader of

colour retinal photographs, using the EURODIAB-Ham-

mersmith grading system [7].

Systolic and diastolic blood pressure were measured for all

diabetic patients in all departments with a semiautomatic

oscillometric meter (Digital blood pressure meter UA-751,

Takeda Medical, Tokyo, Japan). The arterial blood pressure

was measured in the sitting and resting position, on the right

arm with an in¯atable cuff size of 140 mm.

Vibration perception threshold (VPT) was measured on the

right great toe by a handheld biothesiometer (Bio-Medical

Instrument Co., Newbury, OH) as previously described [8, 9].

L

Figure 1 Flow diagram for the patients participating in the Danish

nationwide cohort investigation.

80 Glycaemic control and complications in adolescence · B. S. Olsen et al.

ã 1999 British Diabetic Association. Diabetic Medicine, 16, 79±85

HbA1c samples and clinical information were obtained

from 339 patients. Of the 339 patients, 320 (94.4%) mailed

samples for urine albumin analysis, 312 (92%) had retinal

photographs performed and 336 (99%) patients were

investigated for diabetic neuropathy.

Statistical analysis

Summary statistics are given as mean 6 SD or median

+ range. Comparison of boys vs. girls were based on two-

sample test statistics (unpaired Student's t-test). Compar-

ison between the participating and the nonparticipating

groups of patients was performed by a multiple logistic

regression analysis. Participation (n = 339) and non-

participation (n = 381) were included as the dependent

variables while age, sex, duration of diabetes, insulin

dose, HbA1c, BMI, blood pressure (all 1987 and 1989)

and logarithmic urinary albumin excretion in 1989 were

included as independent variables. The presence of micro

and macroalbuminuria, diabetic retinopathy and elevated

VPT (dependent variables) was evaluated by a backward

stepwise logistic regression analysis including sex, age,

diabetes duration, systolic and diastolic blood pressure,

height, weight and BMI (independent variables). Variables

were included when the likelihood ratio P-value was

below 0.05.

Results

To evaluate potential selection bias between the group of

patients participating in the study and the nonparticipating

group, a multiple logistic regression analysis was performed.

The analysis showed that age (P < 0.05) and the HbA1c values

(1989) (P < 0.01) of the nonparticipating group of patients

were signi®cantly higher compared to the participating group.

The regression coef®cient for age was 0.062 per year (SE

0.025), corresponding to an odds ratio of 1.06 per year. The

regression coef®cient for HbA1c was 0.150 per percentage (SE

0.046), corresponding to an odds ratio of 1.16 per percentage.

Figure 2 shows the relative frequency distribution of HbA1c

in the group studied. The mean HbA1c value was 9.7 6 1.7%

(nondiabetic range 4.3±5.8%, mean 5.3%). Only 11.2% of

the patients had HbA1c values below 8% (10.0% of the males

and 12.6% of the females), despite the fact that 88% of the

patients were treated with three or more daily insulin

injections. Males had higher HbA1c values (P < 0.01) and

received more insulin 0.94 6 0.25 U/kg per 24 h than females

0.90 6 0.26 U/kg per 24 h (P < 0.05).

R

Figure 2 Percentage distribution of HbA1c values in 159 females (h) and 180 males (j).

Epidemiology 81


Microalbuminuria (AER > 20 ± 150 mg/min) was found in

9.0% of patients (the youngest of whom was 15.3 years).

Macroalbuminuria (AER > 150 mg/min) was present in 3.7%

of the patients (youngest patient 19.1 years). Thirty per cent of

the patients with microalbuminuria and 50% of the patients

with macroalbuminuria were being treated with ACE

inhibitors or other antihypertensive medication. Multiple

logistic regression analysis showed that elevated AER was

associated with increased diastolic blood pressure (P < 0.01)

and the severity of diabetic retinopathy (P < 0.01). In patients

with normal as well as elevated AER, the prevalence and

severity of diabetic retinopathy increased with the duration of

L

Figure 3 The relationship between diabetes

duration and severity of diabetic retinopa-

thy in patients with and without elevated

AER. Due to the relatively small number

of patients with severe retinopathy, the

patients are divided into 3 retinopathy

groups, level 0, level 1 and level 2 + (level

2 + includes level 2,3 and 4 retinopathy).

Figure 4 Percentage distribution of diabetic

retinopathy in 320 young persons with

Type 1 DM.

82 Glycaemic control and complications in adolescence · B. S. Olsen et al.


diabetes but subjects with elevated AER had a higher

prevalence of diabetic retinopathy and developed more severe

levels of retinopathy (P < 0.001) (Fig. 3).

Diabetic retinopathy was present in 57.6% of the patients.

Most of the patients (45%) had minimal nonproliferative

retinopathy (level 1, the youngest patient was 12.1 years). Of

the patients, 9.9% (n = 31) had moderate nonproliferative

retinopathy (level 2, youngest patient 17 years). Severe

nonproliferative or preproliferative retinopathy (level 3) was

demonstrated in 2.6% of the patients (n = 9, youngest

22.3 years). One male patient, age 21.8 years and diabetes

duration 10.3 years, had proliferative retinopathy (Fig. 4). For

diabetic retinopathy the risk determinants were age

(P < 0.01)(Table 1), long diabetes duration (P < 0.01), in-

creased HbA1c (P < 0.05), increased AER (P < 0.01) and

elevated diastolic blood pressure (P < 0.01).

Elevated VPT (> 6.5 V) was found in 62.5% of the patients,

of whom the youngest was 15.3 years. In multiple logistic

regression analysis elevated vibration perception threshold

was associated with age (P < 0.01) (Table 1), duration of

diabetes (P < 0.01), height (P < 0.01), diastolic blood pressure

(P < 0.01) and diabetic retinopathy (P = 0.01). Figure 5 shows

the gradual increase in the prevalence of diabetic retinopathy

and neuropathy with longer duration of the disease. As shown

in the ®gure the prevalence of elevated AER did not change

signi®cantly with duration.

Discussion

Between 1987 and 1995, a cohort of young Danish Type 1

diabetic patients was studied on three occasions (1987, 1989

and 1995) for metabolic control and the development of

microvascular complications [3±5]. Only half of the original

cohort (1987 and 1989) agreed to participate in the 1995

follow-up investigation (Fig. 1). As nonparticipating patients

had the highest HbA1c values in 1989, it is possible that the

present results would have been even more unfavourable if all

patients had been included in the study.

Puberty is characterized by relative insulin resistance [9] and

near-normoglycaemia may be dif®cult to achieve in this

R

Figure 5 Percentage distribution of elevated

AER, diabetic retinopathy and elevated

VPT in relation to diabetes duration in

young patients with Type 1 DM.

Age 10±15 years Age 15±20 years Age > 20 years

Mean AER < 20 mg/min 20 (100%) 94 (87.2%) 165 (85.9%)

Mean AER > 20 < 150 mg/min 0 (0%) 11 (10.1%) 18 (9.4%)

Mean AER > 150 mg/min 0 (0%) 3 (2.7%) 9 (4.7%)

Total 20 (100%) 108 (100%) 192 (100%)

Retinopathy level 0 16 (84.2%) 57 (55.3%) 59 (31.1%)

Retinopathy level 1 3 (15.8%) 44 (42.7%) 93 (48.9%)

Retinopathy level 2 + 0 (0%) 2 (2.0%) 38 (20.0%)

Total 19 (100%) 103 (100%) 190 (100%)

Vibration perception

threshold < 6.5 V 19 (95.0%) 59 (53.2%) 48 (23.4%)

Vibration perception

threshold > 6.5 V 1 (5.0%) 52 (46.8%) 157 (76.6%)

Total 20 (100%) 111 (100%) 205 (100%)

Table 1 Number of patients with diabetic

nephropathy, retinopathy and neuropathy in

relation to age. Due to the relatively small

number of patients with level 2±4

retinopathy, the patients are divided into

three retinopathy groups, level 0, level 1 and

level 2 +

Epidemiology 83


period. The mean HbA1c of our 1995 cohort was 9.7% and

very few patients had values below 8%. The overall glycaemic

control (mean HbA1c) was comparable to conventionally

treated adolescents in the DCCT study [1,2]. Strict metabolic

control is associated with a reduced risk for the development

of complications to diabetes [1,2] and, in keeping with other

studies, incipient diabetic complications are already detect-

able in adolescence [4,8,10±12]. It is therefore mandatory to

achieve the best possible glycaemic control from childhood

and adolescence and to screen for diabetic complications in

kidneys, eyes and nerves on a regular basis.

Diabetic nephropathy is a leading cause of increased

morbidity and mortality in patients with Type 1 DM

[13,14]. Microalbuminuria, an early predictor for diabetic

nephropathy and is rarely detected before puberty and in

adolescence its prevalence varies from 4% to 20%

[4,11,13,15], depending on the patient population and the

screening method. In the present study the prevalence of

elevated AER was 13%. The reported relationship between

arterial hypertension and poor glycaemic control and the

presence and progression of microalbuminuria was veri®ed by

our data [4,11,13,16,17]. It is, however, controversial

whether hypertension precedes or succeeds microalbuminuria

[18,19]. Therapy with angiotensin-converting enzyme (ACE)

inhibitors has been shown to reduce AER and delay the

progression to overt diabetic nephropathy in diabetic patients

with persistent microalbuminuria [20,21]. Only a third of our

patients with microalbuminuria and half of those with

macroalbuminuria were treated with ACE inhibitors. A

reason for the lack of treatment could be that some of the

patients had intermittent rather than persistent microalbumi-

nuria. It still remains to be proven whether normotensive

children and adolescents with microalbuminuria should be

treated with ACE-inhibitors [22].

The prevalence of diabetic retinopathy in children and

adolescents varies from 10% to 50% in different studies and

the most prominent risk-factors for diabetic retinopathy are

poor glycaemic control and long duration of diabetes

[12,23,24]. Our data are more consistent with those of

d'Annujio et al. where 80% of young diabetic patients

developed diabetic retinopathy after 14 years of diabetes

[25], as 60% of our patients had diabetic retinopathy. The

majority had minimal changes with only few haemorrhages

and microaneurysms, but 13% of the young patients had more

severe degrees.

Recent studies have shown that subclinical peripheral

neuropathy is detectable in even young patients with Type 1

DM [8,26,27]. In a recent Danish study, 20% of young

asymptomatic diabetic patients had VPT values (big toe)

above the 95% percentile (6.5 V) for age-matched nondiabetic

individuals [8]. More than 60 percentage of our patients had

VPT values above 6.5 V and in keeping with other studies

[8,28,29] was elevated VPT associated with age, diabetes

duration and height. Dyck et al. have previously emphasized

that at least two evaluations of the nervous system be

abnormal to diagnose diabetic neuropathy [30] but biothe-

siometry has been shown to be an easy and reliable method for

assessment of large ®bre dysfunction [8,30] and to give

reproducible results [31]. It is a suitable screening method for

large multicentre investigations although it remains to be

established if subclinical diabetic neural abnormalities are a

valid predictor for the development of clinical manifest

neuropathy.

The natural history of microvascular and neurological

diabetic complications of the complications is thought to be

closely associated, but whether there is a parallel development

of abnormalities in different tissues or an interdependent

pathogenesis is not established [22,32]. Our study showed

signi®cant correlations between elevated AER and diabetic

retinopathy and between elevated VPT and retinopathy. It was

also demonstrated that patients with elevated AER had more

serious retinopathy than normoalbuminuric patients.

We conclude that glycaemic control of young Danish

diabetic patients is poor and microvascular complications to

diabetes are prevalent. To optimize metabolic control and

prevent complications is a priority, with a need for the

development of common guidelines, quality indicators and

educational material for the future treatment of young people

with diabetes.

Acknowledgements

We are grateful to the nurses and photographers at all

departments for excellent assistance during the study. We

specially thank photographer Norman Nielsen and the nurses

(in alphabetic order): I. Brùndum (Randers), K. Dyrlùv

(Glostrup), M. Harrestrup (Viborg), J. Hùjgaard (Odense),

M. Jepsen (Kolding), A.B. Jùrgensen (Esbjerg), K. Kryl

(Holbñk), B. Lange (Nñstved), H. Larsen (Frederikshavn),

I. Lund (Sundby), T. Madsen (Herning), P. Mortensen

(Roskilde), J. Mùldrup (Viborg),T. Nielsen (Hvidovre), P.

Nùrrevang (Hillerùd), L. Nybo (Hillerùd), S. Olesen (Sùnder-

borg), B. Peier (AÊ rhus), L.Povlsen (Glostrup), B. Storm

(Steno), H. Voght (AÊ lborg), A. Vñdele (Odense), P. Werngren

(N. Falster), and I. Yde (Hjùrring) for excellent technical

assistance. The study was kindly supported by grants from

Novo Nordisk.

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REpidemiology 85


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